EP3294732B1 - Benzimidazole and imadazopyridine carboximidamide compounds having activity as inhibitors of indoleamine 2,3-dioxygenase - Google Patents

Benzimidazole and imadazopyridine carboximidamide compounds having activity as inhibitors of indoleamine 2,3-dioxygenase Download PDF

Info

Publication number
EP3294732B1
EP3294732B1 EP16730065.6A EP16730065A EP3294732B1 EP 3294732 B1 EP3294732 B1 EP 3294732B1 EP 16730065 A EP16730065 A EP 16730065A EP 3294732 B1 EP3294732 B1 EP 3294732B1
Authority
EP
European Patent Office
Prior art keywords
hydroxy
carboximidamide
fluorophenyl
chloro
amino
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
EP16730065.6A
Other languages
German (de)
French (fr)
Other versions
EP3294732A1 (en
Inventor
Mark J. BARTLETT
Julian Andrew CODELLI
Britton Kenneth CORKEY
Jennifer Leigh COSMAN
Kristyna ELBEL
Jennifer Alissa Loyer-Drew
David Sperandio
Joshua Van Veldhuizen
Hai Yang
Suet Chung YEUNG
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Gilead Sciences Inc
Original Assignee
Gilead Sciences Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Gilead Sciences Inc filed Critical Gilead Sciences Inc
Publication of EP3294732A1 publication Critical patent/EP3294732A1/en
Application granted granted Critical
Publication of EP3294732B1 publication Critical patent/EP3294732B1/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/538—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with carbocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5386—1,4-Oxazines, e.g. morpholine spiro-condensed or forming part of bridged ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/541—Non-condensed thiazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/12—Ophthalmic agents for cataracts
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D235/08—Radicals containing only hydrogen and carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D235/12—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D235/14—Radicals substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D235/16—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C07D235/28—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C07D235/30—Nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/125—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present disclosure relates generally to inhibitors of indoleamine 2,3-dioxygenase 1 (IDO1) activity and their use and manufacture thereof.
  • IDO1 indoleamine 2,3-dioxygenase 1
  • IDO1 indoleamine 2,3-dioxygenase 1
  • IDO1 catalyzes the degradation of tryptophan to kynurenine, and its effects on immune suppression are due to decreased tryptophan availability and the generation of tryptophan metabolites resulting in multipronged negative effects on cytotoxic T lymphocytes, as well as expansion of immunosuppressive regulatory T cells.
  • IDO1 is elevated in multiple cancers, is induced by chemotherapy, targeted therapy, or immunotherapy. IDO1 expression in the tumor microenvironment is correlated with poor prognosis in a variety of cancers.
  • IDO1 inhibitors are positioned to potentiate the efficacy of multiple oncology therapeutics including immunotherapies, targeted agents, and chemotherapies. Indeed, epacadostat (INCB24360), a potent and selective IDO1 inhibitor, entered clinical trials and is demonstrating activity in combination with ipilimumab (anti-CTLA4) in melanoma.
  • epacadostat ICCB24360
  • anti-CTLA4 ipilimumab
  • IDO1 has been shown to play a role in chronic infections, HIV and AIDS, autoimmune diseases or disorders (e.g., rheumatoid arthritis), and immunologic tolerance, prevention of fetal rejection in utero. Inhibition of IDO1 may also be an important treatment strategy for patients with neurological or neuropsychiatric diseases or disorders, such as depression.
  • WO2015/002918 and WO2014/159248 disclose heteroaryl compounds having activity as inhibitors of indoleamine 2,3-dioxygenase.
  • the present disclosure provides compounds that function as inhibitors of IDO1.
  • the disclosure also provides compositions, including pharmaceutical compositions, kits that include the compounds, and methods of making the compounds.
  • the compounds provided herein are useful in treating diseases, disorders, or conditions that are mediated by IDO1.
  • the disclosure also provides compounds for use in therapy.
  • the disclosure further provides compounds for use in a method of treating a disease, disorder, or condition that is mediated by IDO1.
  • the disclosure provides uses of the compounds in the manufacture of a medicament for the treatment of a disease, disorder or condition that is mediated by IDO1.
  • Some embodiments provide the compounds of formula I for use in the treatment of a disease or condition in a mammal, particularly a human, that is amenable to treatment by an IDO1 inhibitor.
  • the disclosure provides pharmaceutical compositions comprising a therapeutically effective amount of a compound of the disclosure (e.g. a compound of Formula I), and at least one pharmaceutically acceptable excipient.
  • a compound of the disclosure e.g. a compound of Formula I
  • at least one pharmaceutically acceptable excipient e.g. a compound of Formula I
  • a dash (“-") that is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, -CONH 2 is attached through the carbon atom.
  • a dash at the front or end of a chemical group is a matter of convenience; chemical groups may be depicted with or without one or more dashes without losing their ordinary meaning.
  • a wavy line drawn through a line in a structure indicates a point of attachment of a group. Unless chemically or structurally required, no directionality is indicated or implied by the order in which a chemical group is written or named.
  • C u-v indicates that the following group has from u to v carbon atoms.
  • C 1-6 alkyl indicates that the alkyl group has from 1 to 6 carbon atoms.
  • references to "about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se.
  • the term “about” includes the indicated amount ⁇ 10%.
  • the term “about” includes the indicated amount ⁇ 5%.
  • the term “about” includes the indicated amount ⁇ 1%.
  • to the term “about X” includes description of "X”.
  • the singular forms "a” and “the” include plural references unless the context clearly dictates otherwise.
  • reference to “the compound” includes a plurality of such compounds and reference to “the assay” includes reference to one or more assays and equivalents thereof known to those skilled in the art.
  • alkyl refers to an unbranched or branched saturated hydrocarbon chain. As used herein, alkyl has 1 to 20 carbon atoms ( i.e., C 1-20 alkyl), 1 to 8 carbon atoms ( i.e ., C 1-8 alkyl), 1 to 6 carbon atoms ( i.e ., C 1-6 alkyl), or 1 to 4 carbon atoms ( i.e ., C 1-4 alkyl).
  • alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl.
  • alkyl residue having a specific number of carbons is named by chemical name or identified by molecular formula, all positional isomers having that number of carbons may be encompassed; thus, for example, "butyl” includes n-butyl (i.e.
  • Alkenyl refers to an aliphatic group containing at least one carbon-carbon double bond and having from 2 to 20 carbon atoms ( i.e ., C 2-20 alkenyl), 2 to 8 carbon atoms ( i.e ., C 2-8 alkenyl), 2 to 6 carbon atoms ( i.e ., C 2-6 alkenyl), or 2 to 4 carbon atoms ( i.e ., C 2-4 alkenyl).
  • alkenyl groups include ethenyl, propenyl, butadienyl (including 1,2-butadienyl and 1,3-butadienyl).
  • Alkynyl refers to an aliphatic group containing at least one carbon-carbon triple bond and having from 2 to 20 carbon atoms ( i.e ., C 2-20 alkynyl), 2 to 8 carbon atoms ( i.e ., C 2-8 alkynyl), 2 to 6 carbon atoms ( i.e ., C 2-6 alkynyl), or 2 to 4 carbon atoms ( i.e ., C 2-4 alkynyl).
  • alkynyl also includes those groups having one triple bond and one double bond.
  • Alkoxy refers to the group “alkyl-O-”. Examples of alkoxy groups include methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy.
  • Hydroalkoxy refers to an alkoxy group as defined above, wherein one or more hydrogen atoms are replaced by a halogen.
  • R is hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein.
  • Examples of acyl include formyl, acetyl, cylcohexylcarbonyl, cyclohexylmethyl-carbonyl, and benzoyl.
  • Amino refers to the group -NR y R z wherein R y and R z are independently selected from the group consisting of hydrogen, alkyl, haloalkyl, aryl, or heteroaryl; each of which may be optionally substituted.
  • Aryl refers to an aromatic carbocyclic group having a single ring (e.g. monocyclic) or multiple rings (e.g. bicyclic or tricyclic) including fused systems.
  • aryl has 6 to 20 ring carbon atoms ( i.e ., C 6-20 aryl), 6 to 12 carbon ring atoms ( i.e ., C 6-2 aryl), or 6 to 10 carbon ring atoms ( i.e ., C 6-10 aryl).
  • Examples of aryl groups include phenyl, naphthyl, fluorenyl, and anthryl.
  • Aryl does not encompass or overlap in any way with heteroaryl defined below. If one or more aryl groups are fused with a heteroaryl ring, the resulting ring system is heteroaryl.
  • Cycloalkyl refers to a saturated or partially saturated cyclic alkyl group having a single ring or multiple rings including fused, bridged, and spiro ring systems.
  • cycloalkyl includes cycloalkenyl groups (i.e. the cyclic group having at least one double bond).
  • cycloalkyl has from 3 to 20 ring carbon atoms ( i.e ., C 3-20 cycloalkyl), 3 to 12 ring carbon atoms ( i.e ., C 3-12 cycloalkyl), 3 to 10 ring carbon atoms ( i.e ., C 3-10 cycloalkyl), 3 to 8 ring carbon atoms ( i.e ., C 3-8 cycloalkyl), or 3 to 6 ring carbon atoms ( i.e ., C 3-6 cycloalkyl).
  • Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • Halogen or “halo” includes fluoro, chloro, bromo, and iodo.
  • Haloalkyl refers to an unbranched or branched alkyl group as defined above, wherein one or more hydrogen atoms are replaced by a halogen. For example, where a residue is substituted with more than one halogen, it may be referred to by using a prefix corresponding to the number of halogen moieties attached.
  • Dihaloalkyl and trihaloalkyl refer to alkyl substituted with two ("di") or three (“tri") halo groups, which may be, but are not necessarily, the same halogen. Examples of haloalkyl include difluoromethyl (-CHF 2 ) and trifluoromethyl (-CF 3 ).
  • Heteroalkyl refers to an alkyl group in which one or more of the carbon atoms (and any associated hydrogen atoms) are each independently replaced with the same or different heteroatomic group.
  • the term “heteroalkyl” includes unbranched or branched saturated chain having carbon and heteroatoms. By way of example, 1, 2 or 3 carbon atoms may be independently replaced with the same or different heteroatomic group.
  • Heteroatomic groups include, but are not limited to, -NR-, -O-, -S-, -S(O)-, - S(O) 2 -, and the like, where R is H, alkyl, aryl, cycloalkyl, heteroalkyl, heteroaryl or heterocyclyl, each of which may be optionally substituted.
  • heteroalkyl groups include -OCH 3 , -CH 2 OCH 3 , -SCH 3 , -CH 2 SCH 3 , -NRCH 3 , and -CH 2 NRCH 3 , where R is hydrogen, alkyl, aryl, arylalkyl, heteroalkyl, or heteroaryl, each of which may be optionally substituted.
  • heteroalkyl include 1 to 10 carbon atoms, 1 to 8 carbon atoms, or 1 to 4 carbon atoms; and 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom.
  • Heteroaryl refers to an aromatic group having a single ring, multiple rings, or multiple fused rings, with one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • heteroaryl include 1 to 20 ring carbon atoms ( i.e ., C 1-20 heteroaryl), 3 to 12 ring carbon atoms ( i.e ., C 3-12 heteroaryl), or 3 to 8 carbon ring atoms ( i.e ., C 3-8 heteroaryl); and 1 to 5 heteroatoms, 1 to 4 heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, oxygen, and sulfur.
  • heteroaryl groups include pyrimidinyl, purinyl, pyridyl, pyridazinyl, benzothiazolyl, and pyrazolyl.
  • Heteroaryl does not encompass or overlap with aryl as defined above.
  • Heterocyclyl or “heterocyclic ring” refers to an unsaturated non-aromatic cyclic alkyl group, with one or more ring heteroatoms independently selected from nitrogen, oxygen and sulfur.
  • heterocyclyl or “heterocyclic ring” refers to rings that are saturated or partially saturated unless otherwise indicated, e.g., in some embodiments “heterocyclyl” or “heterocyclic ring” refers to rings that are partially saturated where specified.
  • the term “heterocyclyl” or “heterocyclic ring” includes heterocycloalkenyl groups ( i.e ., the heterocyclyl group having at least one double bond).
  • a heterocyclyl may be a single ring or multiple rings wherein the multiple rings may be fused, bridged, or spiro.
  • heterocyclyl has 2 to 20 ring carbon atoms ( i.e., C 2-20 heterocyclyl), 2 to 12 ring carbon atoms ( i.e ., C 2-12 heterocyclyl), 2 to 10 ring carbon atoms ( i.e ., C 2-10 heterocyclyl), 2 to 8 ring carbon atoms ( i.e ., C 2-8 heterocyclyl), 3 to 12 ring carbon atoms ( i.e ., C 3-12 heterocyclyl), 3 to 8 ring carbon atoms ( i.e ., C 3-8 heterocyclyl), or 3 to 6 ring carbon atoms ( i.e ., C 3-6 heterocyclyl); having 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, 1
  • heterocyclyl groups include pyrrolidinyl, piperidinyl, piperazinyl, oxetanyl, dioxolanyl, azetidinyl, and morpholinyl.
  • bridged- heterocyclyl refers to a four- to ten-membered cyclic moiety connected at two non-adjacent atoms of the heterocyclyl with one or more ( e.g ., 1 or 2) four- to ten-membered cyclic moiety having at least one heteroatom where each heteroatom is independently selected from nitrogen, oxygen, and sulfur.
  • bridged-heterocyclyl includes bicyclic and tricyclic ring systems.
  • spiro-heterocyclyl refers to a ring system in which a three- to ten-membered heterocyclyl has one or more additional ring, wherein the one or more additional ring is three- to ten-membered cycloalkyl or three- to ten-membered heterocyclyl, where a single atom of the one or more additional ring is also an atom of the three- to ten-membered heterocyclyl.
  • spiro-heterocyclyl examples include bicyclic and tricyclic ring systems, such as 2-oxa-7-azaspiro[3.5]nonanyl, 2-oxa-6-azaspiro[3.4]octanyl, and 6-oxa-1-azaspiro[3.3]heptanyl.
  • Sulfonyl refers to the group -S(O) 2 R, where R is alkyl, haloalkyl, heterocyclyl, cycloalkyl, heteroaryl, or aryl. Examples of sulfonyl are methylsulfonyl, ethylsulfonyl, phenylsulfonyl, and toluenesulfonyl.
  • a divalent group such as a divalent “alkyl” group, a divalent “aryl” group, etc.
  • a divalent group such as a divalent “alkyl” group, a divalent “aryl” group, etc.
  • combinations of groups are referred to herein as one moiety, e.g . arylalkyl, the last mentioned group contains the atom by which the moiety is attached to the rest of the molecule.
  • substituted means that any one or more hydrogen atoms on the designated atom or group is replaced with one or more substituents other than hydrogen, provided that the designated atom's normal valence is not exceeded.
  • the one or more substituents include, but are not limited to, alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amido, amidino, aryl, azido, carbamoyl, carboxyl, carboxyl ester, cyano, guanidino, halo, haloalkyl, heteroalkyl, heteroaryl, heterocyclyl, hydroxy, hydrazino, imino, oxo, nitro, alkylsulfinyl, sulfonic acid, alkylsulfonyl, thiocyanate, thiol, thione, or combinations thereof.
  • impermissible substitution patterns e.g., methyl substituted with 5 fluorines or heteroaryl groups having two adjacent oxygen ring atoms.
  • impermissible substitution patterns are well known to the skilled artisan.
  • substituted may describe other chemical groups defined herein.
  • substituted aryl includes, but is not limited to, "alkylaryl.” Unless specified otherwise, where a group is described as optionally substituted, any substituents of the group are themselves unsubstituted.
  • substituted alkyl refers to an alkyl group having one or more substituents including hydroxyl, halo, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl.
  • substituted cycloalkyl refers to a cycloalkyl group having one or more substituents including alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, halo, oxo, and hydroxyl
  • substituted heterocyclyl refers to a heterocyclyl group having one or more substituents including alkyl, haloalkyl, heterocyclyl, cycloalkyl, aryl, heteroaryl, alkoxy, halo, oxo, and hydroxyl
  • substituted aryl refers to an aryl group having one or more substituents including halo, alkyl, haloalkyl, cycloalkyl, heterocyclyl, heteroaryl, alkoxy, and cyano
  • substituted heteroaryl refers to an heteroaryl group having one or more substituents including alkyl, haloalkyl, cycloalkyl, hetero
  • the one or more substituents may be further substituted with halo, alkyl, haloalkyl, hydroxyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is substituted.
  • the substituents may be further substituted with halo, alkyl, haloalkyl, alkoxy, hydroxyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is unsubstituted.
  • Tautomeric isomers are in equilibrium with one another.
  • amide containing compounds may exist in equilibrium with imidic acid tautomers. Regardless of which tautomer is shown, and regardless of the nature of the equilibrium among tautomers, the compounds are understood by one of ordinary skill in the art to comprise both amide and imidic acid tautomers. Thus, the amide containing compounds are understood to include their imidic acid tautomers. Likewise, the imidic acid containing compounds are understood to include their amide tautomers.
  • any formula or structure given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds.
  • Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number.
  • isotopes that can be incorporated into compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as, but not limited to 2 H (deuterium, D), 3 H (tritium), 11 C, 13 C, 14 C, 15 N, 18 F, 31 P, 32 P, 35 S, 36 Cl and 125 I.
  • isotopically labeled compounds of the present disclosure for example those into which radioactive isotopes such as 3 H, 13 C and 14 C are incorporated.
  • isotopically labelled compounds may be useful in metabolic studies, reaction kinetic studies, detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays or in radioactive treatment of patients.
  • PET positron emission tomography
  • SPECT single-photon emission computed tomography
  • the disclosure also included compounds of Formula I in which from 1 to n hydrogens attached to a carbon atom is/are replaced by deuterium, in which n is the number of hydrogens in the molecule.
  • Such compounds exhibit increased resistance to metabolism and are thus useful for increasing the half-life of any compound of Formula I when administered to a mammal, particularly a human. See, for example, Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism," Trends Pharmacol. Sci. 5(12):524-527 (1984 ).
  • Such compounds are synthesized by means well known in the art, for example by employing starting materials in which one or more hydrogens have been replaced by deuterium.
  • Deuterium labelled or substituted therapeutic compounds of the disclosure may have improved DMPK (drug metabolism and pharmacokinetics) properties, relating to distribution, metabolism and excretion (ADME). Substitution with heavier isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life, reduced dosage requirements and/or an improvement in therapeutic index.
  • An 18 F labeled compound may be useful for PET or SPECT studies.
  • Isotopically labeled compounds of this disclosure and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent. It is understood that deuterium in this context is regarded as a substituent in the compound of Formula I.
  • the concentration of such a heavier isotope, specifically deuterium may be defined by an isotopic enrichment factor.
  • any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom.
  • a position is designated specifically as “H” or “hydrogen”, the position is understood to have hydrogen at its natural abundance isotopic composition.
  • any atom specifically designated as a deuterium (D) is meant to represent deuterium.
  • the compounds of this disclosure are capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto.
  • pharmaceutically acceptable salt of a given compound refers to salts that retain the biological effectiveness and properties of the given compound, and which are not biologically or otherwise undesirable.
  • Pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. Salts derived from inorganic bases include, by way of example only, sodium, potassium, lithium, ammonium, calcium and magnesium salts.
  • Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines, such as alkyl amines, dialkyl amines, trialkyl amines, substituted alkyl amines, di(substituted alkyl) amines, tri(substituted alkyl) amines, alkenyl amines, dialkenyl amines, trialkenyl amines, substituted alkenyl amines, di(substituted alkenyl) amines, tri(substituted alkenyl) amines, mono, di or tri cycloalkyl amines, mono, di or tri arylamines or mixed amines, etc.
  • primary, secondary and tertiary amines such as alkyl amines, dialkyl amines, trialkyl amines, substituted alkyl amines, di(substituted alkyl) amines, tri
  • Suitable amines include, by way of example only, isopropylamine, trimethyl amine, diethyl amine, tri(iso-propyl) amine, tri(n-propyl) amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like.
  • Salts derived from inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
  • Salts derived from organic acids include acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluene-sulfonic acid, salicylic acid, and the like.
  • pharmaceutically acceptable carrier or “pharmaceutically acceptable excipient” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like.
  • the use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions.
  • Treatment is an approach for obtaining beneficial or desired results including clinical results.
  • beneficial or desired clinical results may include one or more of the following: a) inhibiting the disease or condition (e.g ., decreasing one or more symptoms resulting from the disease or condition, and/or diminishing the extent of the disease or condition); b) slowing or arresting the development of one or more clinical symptoms associated with the disease or condition (e.g ., stabilizing the disease or condition, preventing or delaying the worsening or progression of the disease or condition, and/or preventing or delaying the spread ( e.g ., metastasis) of the disease or condition); and/or c) relieving the disease, that is, causing the regression of clinical symptoms (e.g ., ameliorating the disease state, providing partial or total remission of the disease or condition, enhancing effect of another medication, delaying the progression of the disease, increasing the quality of life, and/or prolonging survival.
  • a) inhibiting the disease or condition e.g ., decreasing one or more symptoms
  • Prevention means any treatment of a disease or condition that causes the clinical symptoms of the disease or condition not to develop.
  • Compounds may, in some embodiments, be administered to a subject (including a human) who is at risk or has a family history of the disease or condition.
  • Subject refers to an animal, such as a mammal (including a human), that has been or will be the object of treatment, observation or experiment. The methods described herein may be useful in human therapy and/or veterinary applications.
  • the subject is a mammal. In one embodiment, the subject is a human.
  • terapéuticaally effective amount or “effective amount” of a compound described herein or pharmaceutically acceptable salts, isomer, or a mixture thereof means an amount sufficient to effect treatment when administered to a subject, to provide a therapeutic benefit such as amelioration of symptoms or slowing of disease progression.
  • a therapeutically effective amount may be an amount sufficient to decrease a symptom of a disease or condition responsive to inhibition of IDO1 activity.
  • the therapeutically effective amount may vary depending on the subject, and disease or condition being treated, the weight and age of the subject, the severity of the disease or condition, and the manner of administering, which can readily be determined by one or ordinary skill in the art.
  • inhibitors indicates a decrease in the baseline activity of a biological activity or process.
  • Inhibition of activity of IDO1 or variants thereof refers to a decrease in activity in IDO1 as a direct or indirect response to the presence of a compound of the present application relative to the activity IDO1 in the absence of the compound of the present application.
  • Inhibition of IDO1 refers to a decrease in IDO1 activity as a direct or indirect response to the presence of a compound described herein relative to the activity of IDO1 in the absence of the compound described herein.
  • the inhibition of IDO1 activity may be compared in the same subject prior to treatment, or other subjects not receiving the treatment.
  • R 1 is bicyclic aryl or heteroaryl optionally substituted with one, two, or three substituents independently selected from hydroxyl, halo, -CN, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1 - 6 alkoxy, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 3-6 cycloalkyl, wherein two of the optional substituents can join to form an additional partially saturated heterocyclic ring; and wherein each C 1-6 alkoxy, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 3-6 cycloalkyl is optionally substituted with one, two, or three substituents independently selected from hydroxyl, halo, -CN, -N(R 20 )(R 22 ), and C 3-6 cycloalkyl.
  • R 1 is bicyclic aryl or heteroaryl optionally substituted with one, two, or three substituents independently selected from hydroxyl, halo, -CN, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 alkoxy, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 3-6 cycloalkyl.
  • the compound is selected from the group consisting of:
  • R 1 is phenyl optionally substituted with one, two, or three substituents independently selected from hydroxyl, halo, -CN, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1 - 6 alkoxy, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 3-6 cycloalkyl, wherein two of the optional substituents can join to form an additional partially saturated heterocyclic ring; and wherein each C 1-6 alkoxy, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 3-6 cycloalkyl is optionally substituted with one, two, or three substituents independently selected from hydroxyl, halo, -CN, -N(R 20 )(R 22 ), and C 3-6 cycloalkyl.
  • R 1 is phenyl optionally substituted with one, two, or three substituents independently selected from hydroxyl, halo, -CN, -CHF 2 , -O-CHF 2 , -CF 3 , -O-CF 3 , C 1 - 4 alkoxy, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, and C 3-6 cycloalkyl, and wherein two of the optional substituents can join to form an additional partially saturated heterocyclic ring.
  • R 2a , R 2b , and, when present, R 2c are not hydrogen.
  • R 2a is not hydrogen.
  • R 2b is not hydrogen.
  • R 2c is not hydrogen.
  • the compound is selected from the group consisting of:
  • L is a bond
  • R t is C 1-6 alkyl optionally substituted with one, two, or three substituents independently selected from hydroxyl, halo, -NO 2 , C 1-6 haloalkyl, C 1-6 haloalkoxy, C 3-6 cycloalkyl, -CN, and C 1-6 alkoxy.
  • the compound is selected from the group consisting of:
  • R t is C 3-15 cycloalkyl, aryl, heteroaryl, or heterocyclyl, wherein said cycloalkyl, aryl, heterocyclyl, or heteroaryl is optionally substituted with one, two, or three substituents independently selected from hydroxyl, halo, -NO 2 , C 1-6 haloalkyl, C 1-6 haloalkoxy, C 3-6 cycloalkyl, -CN, C 1-6 alkoxy and C 1-6 alkyl.
  • the compound is selected from the group consisting of:
  • R t is hydrogen
  • the compound is selected from the group consisting of:
  • L is -NR 3 .
  • R t is C 1-6 optionally substituted with one, two, or three substituents independently selected from hydroxyl, halo, -NO 2 , C 1-6 haloalkyl, C 1-6 haloalkoxy, -N(R 20 )(R 22 ), -SO 2 R 20 , C 3-6 cycloalkyl, -CN, and C 1-6 alkoxy.
  • the compound is selected from the group consisting of:
  • L is -NR 3 and R t is C 3-15 cycloalkyl, aryl, heteroaryl, or heterocyclyl, wherein said cycloalkyl, aryl, heterocyclyl, or heteroaryl is optionally substituted with one, two, or three substituents independently selected from hydroxyl, halo, -NO 2 , C 1-6 haloalkyl, C 1-6 haloalkoxy, C 3-6 cycloalkyl, -CN, and C 1-6 alkoxy.
  • the compound is selected from the group consisting of:
  • L is -NR 3 and R t is hydrogen.
  • the compound is selected from the group consisting of:
  • L is -SO 2 NR 3 -.
  • the compound is selected from the group consisting of:
  • X is -N-.
  • X is -CR 2c -.
  • the compound is selected from the group consisting of:
  • L is -C(O)-NR 3 -.
  • the compound is selected from the group consisting of:
  • L is N, m is 1, and n is 0.
  • L is N, m is 2, and n is 0.
  • L is N, m is 3, and n is 0.
  • the compound of Formula I is represented by Formula IA or IB:
  • R 1 is selected from the group consiting of and
  • R 1 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • the compound of Formula I is represented by Formula II:
  • the compound of Formula I is represented by Formula IIA or IIB:
  • the compound of Formula I is represented by Formula III:
  • the compound of Formula I is represented by Formula IV:
  • the group of any Formula described herein is selected from the group consisting of hydrogen, (1-methylpiperidin-2-yl)methylamino, (1-methylpyrrolidin-3-yl)amino, (2-pyrimidin-2-ylethylamino)methyl, (2S)-pyrrolidin-2-yl, (isopropyloxycarbonyl)amino, (1,3-thiazol-2-ylmethylamino)methyl, 1H-imidazol-2-yl, 1H-pyrazol-5-yl, 1H-pyrrol-2-yl, 1-hydroxyethyl, 2-(2-methoxyethylamino)ethyl, 2-(diethylamino)ethyl, 2-(diethylamino)ethylamino, 2-(dimethylamino)-1-hydroxyethyl, 2-(dimethylamino)ethyl, 2-(dimethylamino)ethylamino, [2-(2-(2-
  • the group of any Formula described herein is selected from the group consisting of: -H,
  • the group of any Formula described herein is selected from the group consisting of: -H, -NH 2 ,
  • the group of any Formula described herein is selected from the group consisting of: -NH 2 ,
  • the compound of Formula I is represented by Formula IIA or IIB:
  • each R 1a is independently hydroxyl, halo, -CN, C 1 - 6 haloalkoxy, or C 1-6 haloalkyl. In some embodiments, each R 1a is independently halo or - CF 3 . In some embodiments, each R 1a is independently halo. In some embodiments, s is 0. In some embodiments, s is 1. In some embodiments, s is 2. In some embodiments, s is 3.
  • Example 10 the compound of Example 10 (shown below) may be referred to as N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide or N-(3-chloro-4-fluorophenyl)-6,7-difluoro-N'-hydroxy-3H-benzimidazole-4-carboximidamide, where both names provide the structure below.
  • Tautomeric isomers are in equilibrium with one another. Regardless of which tautomer is shown, and regardless of the nature of the equilibrium among tautomers, the compounds are understood by one of ordinary skill in the art to comprise both.
  • Non-limiting examples of benzimidazole and imidazo[4,5-b]pyridine tautomers are shown below:
  • n hydrogen atoms attached to a carbon atom may be replaced by a deuterium atom or D, in which n is the number of hydrogen atoms in the molecule.
  • the deuterium atom is a non-radioactive isotope of the hydrogen atom.
  • Such compounds may increase resistance to metabolism, and thus may be useful for increasing the half-life of the compounds described herein or pharmaceutically acceptable salts, isomer, or a mixture thereof when administered to a mammal. See, e.g ., Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism", Trends Pharmacol. Sci., 5(12):524-527 (1984 ).
  • Such compounds are synthesized by means well known in the art, for example by employing starting materials in which one or more hydrogen atoms have been replaced by deuterium.
  • “Pharmaceutically acceptable” or “physiologically acceptable” refer to compounds, salts, compositions, dosage forms and other materials which are useful in preparing a pharmaceutical composition that is suitable for veterinary or human pharmaceutical use.
  • “Pharmaceutically acceptable salts” or “physiologically acceptable salts” include, for example, salts with inorganic acids and salts with an organic acid.
  • the free base can be obtained by basifying a solution of the acid salt.
  • an addition salt particularly a pharmaceutically acceptable addition salt
  • a suitable organic solvent may be used to prepare nontoxic pharmaceutically acceptable addition salts.
  • a “solvate” is formed by the interaction of a solvent and a compound. Solvates of salts of the compounds described herein are also provided. Hydrates of the compounds described herein are also provided.
  • a “prodrug” is a biologically inactive derivative of a drug that upon administration to the human body is converted to the biologically active parent drug according to some chemical or enzymatic pathway.
  • optical isomers, racemates, or other mixtures thereof of the compounds described herein or pharmaceutically acceptable salts or a mixture thereof can be obtained by asymmetric synthesis or by resolution of the racemate. Resolution of racemates can be accomplished, for example, by conventional methods such as crystallization in the presence of a resolving agent, or chromatography, using, for example a chiral high pressure liquid chromatography (HPLC) column.
  • Z- and E- forms or cis- and trans- forms of the hydroxyamidine compounds described herein. Specifically, Z- and E- forms are included even if only one designation is named for both carbon-carbon double bonds as well as the hydroxyamidine bond.
  • compositions provided herein that include a compound described herein or pharmaceutically acceptable salts, or a mixture thereof may include racemic mixtures, or mixtures containing an enantiomeric excess of one enantiomer or single diastereomers or diastereomeric mixtures. All such isomeric forms of these compounds are expressly included herein the same as if each and every isomeric form were specifically and individually listed.
  • provided herein are also crystalline and amorphous forms of the compounds described herein or pharmaceutically acceptable salts, isomer, or a mixture thereof.
  • chelates are also chelates, non-covalent complexes, and mixtures thereof, of the compounds described herein or pharmaceutically acceptable salts, or a mixture thereof.
  • a "chelate” is formed by the coordination of a compound to a metal ion at two (or more) points.
  • a “non-covalent complex” is formed by the interaction of a compound and another molecule wherein a covalent bond is not formed between the compound and the molecule. For example, complexation can occur through van der Waals interactions, hydrogen bonding, and electrostatic interactions (also called ionic bonding).
  • the methods described herein may be applied to cell populations in vivo or ex vivo.
  • In vivo means within a living individual, as within an animal or human. In this context, the methods described herein may be used therapeutically in an individual.
  • Ex vivo means outside of a living individual. Examples of ex vivo cell populations include in vitro cell cultures and biological samples including fluid or tissue samples obtained from individuals. Such samples may be obtained by methods well known in the art. Exemplary biological fluid samples include blood, cerebrospinal fluid, urine, and saliva. Exemplary tissue samples include tumors and biopsies thereof. In this context, the invention may be used for a variety of purposes, including therapeutic and experimental purposes.
  • the invention may be used ex vivo to determine the optimal schedule and/or dosing of administration of an IDOl inhibitor for a given indication, cell type, individual, and other parameters. Information gleaned from such use may be used for experimental purposes or in the clinic to set protocols for in vivo treatment. Other ex vivo uses for which the invention may be suited are described below or will become apparent to those skilled in the art.
  • the selected compounds may be further characterized to examine the safety or tolerance dosage in human or non-human subjects. Such properties may be examined using commonly known methods to those skilled in the art.
  • the compounds described herein may be used to treat subjects who have or are suspected of having disease states, disorders, and conditions (also collectively referred to as "indications") responsive or believed to be responsive to the inhibition of IDO1 activity.
  • the compounds described herein may be used to inhibit the activity of an IDOl polypeptide.
  • the compounds described herein may be used to inhibit excessive or destructive immune reactions or growth or a proliferation of a cell, such as a cancer cell, or inhibit immunosuppression.
  • Example indications suitable for treatment with compounds described here include, without limitation cancer, viral infection such as HIV infection, HBV infection, HCV infection, other infections (e.g., skin infections, GI infection, urinary tract infections, genito-urinary infections, and systemic infections), depression, neurodegenerative disorders such as Alzheimer's disease and Huntington's disease, trauma, age-related cataracts, organ transplantation ( e.g ., organ transplant rejection), and autoimmune diseases.
  • viral infection such as HIV infection, HBV infection, HCV infection
  • other infections e.g., skin infections, GI infection, urinary tract infections, genito-urinary infections, and systemic infections
  • depression e.g., neurodegenerative disorders such as Alzheimer's disease and Huntington's disease, trauma, age-related cataracts, organ transplantation (e.g ., organ transplant rejection), and autoimmune diseases.
  • autoimmune diseases include, but are not limited to, asthma, collagen diseases such as rheumatoid arthritis, systemic lupus erythematosus. Sharp's syndrome, CREST syndrome (calcinosis, Raynaud's syndrome, esophageal dysmotility, sclerodactyly, telangiectasia), dermatomyositis, vasculitis (Morbus Wegener's) and Sjögren's syndrome, renal diseases such as Goodpasture's syndrome, rapidly- progressing glomerulonephritis and membrano-proliferative glomerulonephritis type II, endocrine diseases such as type-I diabetes, autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), autoimmune parathyroidism, pernicious anemia, gonad insufficiency, idiopathic Morbus Addison's, hyperthyreosis, Hashimoto
  • the compounds described herein may be used for treating cancer, viral infection, depression, a neurodegenerative disorder, trauma, age-related cataracts, organ transplant rejection, or an autoimmune disease.
  • the disease to be treated is a solid tumor.
  • the solid tumor is from pancreatic cancer, bladder cancer, colorectal cancer, breast cancer, prostate cancer, renal cancer, hepatocellular cancer, lung cancer, ovarian cancer, cervical cancer, gastric cancer, esophageal cancer, head and neck cancer, melanoma, neuroendocrine cancers, CNS cancers, brain tumors (e.g., glioma, anaplastic oligodendroglioma, adult glioblastoma multiforme, and adult anaplastic astrocytoma), bone cancer, or soft tissue sarcoma.
  • the solid tumor is from non-small cell lung cancer, small-cell lung cancer, colon cancer, CNS cancer, melanoma, ovarian cancer, renal cancer, prostate cancer, or breast cancer..
  • the disease is an autoimmune disease.
  • the autoimmune disease is systemic lupus erythematosus (SLE), myestenia gravis, rheumatoid arthritis (RA), acute disseminated encephalomyelitis, idiopathic thrombocytopenic purpura, multiple sclerosis (MS), psoriasis, Sjoegren's syndrome, psoriasis, autoimmune hemolytic anemia, asthma, or chronic obstructive pulmonary disease (COPD).
  • the disease is inflammation.
  • the disease is excessive or destructive immune reactions, such as asthma, rheumatoid arthritis, multiple sclerosis, chronic obstructive pulmonary disease (COPD), and lupus.
  • a compound of formula I for use in a method for treating a subject, who has or is suspected of having a disease or condition responsive or believed to be responsive to the inhibition of IDO1 activity by administering to the subject the compound described herein or pharmaceutically acceptable salts, or a mixture thereof.
  • a method of inhibiting kinase activity of a IDO1 polypeptide by contacting the polypeptide with the compound described herein or pharmaceutically acceptable salts, isomer, or a mixture thereof.
  • a compound of formula I for use in a method of inhibiting a growth or a proliferation of cancer cells of hematopoietic origin comprising contacting the cancer cells with an effective amount of a compound described herein or pharmaceutically acceptable salts, isomer, or a mixture thereof.
  • the compounds of the present application may be used in combination with one or more additional therapeutic agent that are being used and/or developed to treat cancers or inflammatory disorders.
  • the one or more additional therapeutic agent may be a chemotherapeutic agent, an immunotherapeutic agent, a radiotherapeutic agent, an anti-neoplastic agent, an anti-cancer agent, an anti-proliferation agent, an anti-fibrotic agent, an anti-angiogenic agent, a therapeutic antibody, or any combination thereof.
  • the one or more additional therapeutic agent may be an inhibitor to PI3K such as PI3K ⁇ , PI3K ⁇ , PI3K ⁇ , and/or PI3K ⁇ , Janus kinase (JAK) such as JAK1, JAK2 and/or JAK3 , spleen tyrosine kinase (SYK), Bruton's tyrosine kinase (BTK), bromodomain containing protein inhibitor (BRD) such as BRD4, a lysyl oxidase protein (LOX), lysyl oxidase-like protein (LOXL) such as LOXL1-5, matrix metalloprotease (MMP) such as MMP 1-10, adenosine A2B receptor (A2B), isocitrate dehydrogenase (IDH) such as IDH1, apoptosis signal-regulating kinase (ASK) such as ASK1, serine/threonine
  • a phosphoinositide 3-kinase inhibitor functions by inhibiting one or more of the phosphoinositide 3-kinase enzymes, including but not limited to PI3K ⁇ , PI3K ⁇ , PI3K ⁇ , and PI3K ⁇ .
  • Non-limiting examples of PI3K inhibitors include wortmannin, demethoxyviridin, LY294002, idelalisib, perifosine, PX-866, IPI-145, BAY 80-6946, BEZ235, RP6530, TGR 1202, INK1117, GDC-0941, BKM120, XL147 (also known as SAR245408), XL765 (also known as SAR245409), Palomid 529, GSK1059615, ZSTK474, PWT33597, IC87114, CAL263, RP6503, PI-103, GNE-477, CUDC-907 and AEZS-136.
  • the PI3K inhibitor is a PI3K ⁇ inhibitors, such as idelalisib, IPI-145, RP6530, and RP6503, as well as those disclosed in U.S. Patent No. 8,569,296 , and PCT publications WO 2014/006572 and WO 2015/001491 .
  • the one or more additional therapeutic agent may be an MMP9 inhibitor, or an agent that inhibits the expression and/or activity of MMP9.
  • a representative protein sequence for MMP9 is GenBank Accession No. NP_004985.
  • the inhibitor can be small molecule or biologic.
  • SB-3CT CAS 292605-14-2 .
  • siRNA, antisense RNA and antibodies have also been demonstrated to inhibit the expression or activity of MMP9 and are within the scope of the present disclosure.
  • an MMP9 inhibitor is a monoclonal anti-MMP9 antibody.
  • the one or more additional therapeutic agent includes an MMP9 inhibitor and a nucleoside analog such as gemcitabine.
  • One, two, three, or more of the therapeutic agents may be further used or combined with a chemotherapeutic agent, an immunotherapeutic agent, a radiotherapeutic agent, an anti-neoplastic agent, an anti-cancer agent, an anti-fibrotic agent, an anti-angiogenic agent, a therapeutic antibody, or any combination thereof.
  • a chemotherapeutic agent an immunotherapeutic agent, a radiotherapeutic agent, an anti-neoplastic agent, an anti-cancer agent, an anti-fibrotic agent, an anti-angiogenic agent, a therapeutic antibody, or any combination thereof.
  • Chemotherapeutic agents may be categorized by their mechanism of action into, for example, the following groups: anti-metabolites/anti-cancer agents, such as pyrimidine analogs (floxuridine, capecitabine, and cytarabine); purine analogs, folate antagonists and related inhibitors, antiproliferative/antimitotic agents including natural products such as vinca alkaloid (vinblastine, vincristine) and microtubule such as taxane (paclitaxel, docetaxel), vinblastin, nocodazole, epothilones and navelbine, epidipodophyllotoxins (etoposide, teniposide); DNA damaging agents (actinomycin, amsacrine, busulfan, carboplatin, chlorambucil, cisplatin, cyclophosphamide, Cytoxan, dactinomycin, daunorubicin, doxorubicin, epirubicin, iphosphamide,
  • chemotherapeutic agent or “chemotherapeutic” (or “chemotherapy,” in the case of treatment with a chemotherapeutic agent) is meant to encompass any non-proteinaceous (i.e., non-peptidic) chemical compound useful in the treatment of cancer.
  • chemotherapeutic agents include alkylating agents such as thiotepa and cyclophosphamide (CYTOXAN); alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; emylerumines and memylamelamines including alfretamine, triemylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide and trimemylolomelamine; acetogenins (especially bullatacin and bullatacinone); a camptothecin (including synthetic analogue topotecan); bryostatin; callystatin; CC-1065 (including its adozelesin, carzelesin and bizelesin synthetic analogues); cryptophycins (articularly cryptophycin 1 and cryptophycin 8); dolastatin; duocar
  • dynemicin including dynemicin A; bisphosphonates, such as clodronate; an esperamicin; as well as neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromomophores), aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, carrninomycin, carzinophilin, chromomycins, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin (including morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin and deoxydoxorubicin), epirubicin, es
  • One or more chemotherapeutic agent are used or included in the present application.
  • gemcitabine, nab-paclitaxel, and gemcitabine/nab-paclitaxel are used with the JAK inhibitor and/or PI3K ⁇ inhibitor for treating hyperproliferative disorders.
  • chemotherapeutic agent anti-hormonal agents that act to regulate or inhibit hormone action on tumors
  • antiestrogens and selective estrogen receptor modulators SERMs
  • SERMs selective estrogen receptor modulators
  • tamoxifen including NolvadexTM
  • raloxifene including NolvadexTM
  • droloxifene 4-hydroxytamoxifen
  • trioxifene keoxifene
  • LY117018 onapristone
  • toremifene Fareston(r)
  • inhibitors of the enzyme aromatase which regulates estrogen production in the adrenal glands, such as, for example, 4(5)-imidazoles, aminoglutethimide, megestrol acetate (Megace(r)), exemestane, formestane, fadrozole, vorozole (Rivisor(r)), letrozole (Femara(r)), and anastrozole (Arimidex(r).
  • anti-androgens
  • the anti-angiogenic agents include, but are not limited to, retinoid acid and derivatives thereof, 2-methoxyestradiol, ANGIOSTATIN(r), ENDOSTATIN(r), suramin, squalamine, tissue inhibitor of metalloproteinase-1, tissue inhibitor of metalloproternase-2, plasminogen activator inhibitor-1, plasminogen activator inhibitor-2, cartilage-derived inhibitor, paclitaxel (nab-paclitaxel), platelet factor 4, protamine sulphate (clupeine), sulfated chitin derivatives (prepared from queen crab shells), sulfated polysaccharide peptidoglycan complex (sp-pg), staurosporine, modulators of matrix metabolism, including for example, proline analogs ((1-azetidine-2-carboxylic acid (LACA), cishydroxyproline, D,L-3,4-dehydroproline, thiaproline, .alpha.-
  • anti-angiogenesis agents include antibodies, preferably monoclonal antibodies against these angiogenic growth factors: beta-FGF, alpha-FGF, FGF-5, VEGF isoforms, VEGF-C, HGF/SF and Ang-1/Ang-2. See Ferrara N. and Alitalo, K. "Clinical application of angiogenic growth factors and their inhibitors" (1999) Nature Medicine 5:1359-1364 .
  • the anti-fibrotic agents include, but are not limited to, the compounds such as beta-aminoproprionitrile (BAPN), as well as the compounds disclosed in U.S. Pat. No. 4,965,288 to Palfreyman, et al., issued Oct. 23, 1990 , entitled "Inhibitors of lysyl oxidase,” relating to inhibitors of lysyl oxidase and their use in the treatment of diseases and conditions associated with the abnormal deposition of collagen; U.S. Pat. No. 4,997,854 to Kagan, et al., issued Mar.
  • BAPN beta-aminoproprionitrile
  • Exemplary anti-fibrotic agents also include the primary amines reacting with the carbonyl group of the active site of the lysyl oxidases, and more particularly those which produce, after binding with the carbonyl, a product stabilized by resonance, such as the following primary amines: emylenemamine, hydrazine, phenylhydrazine, and their derivatives, semicarbazide, and urea derivatives, aminonitriles, such as beta-aminopropionitrile (BAPN), or 2-nitroethylamine, unsaturated or saturated haloamines, such as 2-bromo-ethylamine, 2-chloroethylamine, 2-trifluoroethylamine, 3-bromopropylamine, p-halobenzylamines, selenohomocysteine lactone.
  • primary amines reacting with the carbonyl group of the active site of the lysyl oxidases, and more particularly those which produce
  • the anti-fibrotic agents are copper chelating agents, penetrating or not penetrating the cells.
  • Exemplary compounds include indirect inhibitors such compounds blocking the aldehyde derivatives originating from the oxidative deamination of the lysyl and hydroxylysyl residues by the lysyl oxidases, such as the thiolamines, in particular D-penicillamine, or its analogues such as 2-amino-5-mercapto-5-methylhexanoic acid, D-2-amino-3-methyl-3-((2-acetamidoethyl)dithio)butanoic acid, p-2-amino-3-methyl-3-((2-aminoethyl)dithio)butanoic acid, sodium-4-((p-1-dimethyl-2-amino-2-carboxyethyl)dithio)butane sulphurate, 2-acetamidoethyl-2-acetamid
  • the immunotherapeutic agents include and are not limited to therapeutic antibodies suitable for treating patients; such as abagovomab, adecatumumab, afutuzumab, alemtuzumab, altumomab, amatuximab, anatumomab, arcitumomab, bavituximab, bectumomab, bevacizumab, bivatuzumab, blinatumomab, brentuximab, cantuzumab, catumaxomab, cetuximab, citatuzumab, cixutumumab, clivatuzumab, conatumumab, daratumumab, drozitumab, duligotumab, dusigitumab, detumomab, dacetuzumab, dalotuzumab, ecromeximab, elotuzumab
  • the application also provides a compound of formula I for use in a method for treating a subject who is undergoing one or more standard therapies, such as chemotherapy, radiotherapy, immunotherapy, surgery, or combination thereof. Accordingly, one or more therapeutic agent or inhibitors may be administered before, during, or after administration of chemotherapy, radiotherapy, immunotherapy, surgery or combination thereof.
  • the subject may be a human who is (i) substantially refractory to at least one chemotherapy treatment, or (ii) in relapse after treatment with chemotherapy, or both (i) and (ii). In some of embodiments, the subject is refractory to at least two, at least three, or at least four chemotherapy treatments (including standard or experimental chemotherapies).
  • the subject is refractory to at least one, at least two, at least three, or at least four chemotherapy treatment (including standard or experimental chemotherapy) selected from fludarabine, rituximab, obinutuzumab, alkylating agents, alemtuzumab and other chemotherapy treatments such as CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone); R-CHOP (rituximab-CHOP); hyperCVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone, methotrexate, cytarabine); R-hyperCVAD (rituximab-hyperCVAD); FCM (fludarabine, cyclophosphamide, mitoxantrone); R-FCM (rituximab, fludarabine, cyclophosphamide, mitoxantrone); bortezom
  • chemotherapy treatment
  • lymphomas Treatment of certain lymphomas is reviewed in Cheson, B.D., Leonard, J.P., “Monoclonal Antibody Therapy for B-Cell Non-Hodgkin's Lymphoma” The New England Journal of Medicine 2008, 359(6), p. 613-626 ; and Wierda, W.G., "Current and Investigational Therapies for Patients with CLL” Hematology 2006, p. 285-294 . Lymphoma incidence patterns in the United States is profiled in Morton, L.M., et al. "Lymphoma Incidence Patterns by WHO Subtype in the United States, 1992-2001” Blood 2006, 107(1), p. 265-276 .
  • immunotherapeutic agents treating lymphoma or leukemia include, but are not limited to, rituximab (such as Rituxan), alemtuzumab (such as Campath, MabCampath), anti-CD 19 antibodies, anti-CD20 antibodies, anti-MN-14 antibodies, anti-TRAIL, Anti-TRAIL DR4 and DR5 antibodies, anti-CD74 antibodies, apolizumab, bevacizumab, CHIR-12.12, epratuzumab (hLL2- anti-CD22 humanized antibody), galiximab, ha20, ibritumomab tiuxetan, lumiliximab, milatuzumab, ofatumumab, PRO131921, SGN-40, WT-1 analog peptide vaccine, WT1 126-134 peptide vaccine, tositumomab, autologous human tumor-derived HSPPC-96, and veltuzumab.
  • Additional immunotherapy agents includes using cancer vaccines
  • chemotherapy agents for treating lymphoma or leukemia include aldesleukin, alvocidib, antineoplaston AS2-1, antineoplaston A10, anti-thymocyte globulin, amifostine trihydrate, aminocamptothecin, arsenic trioxide, beta alethine, Bcl-2 family protein inhibitor ABT-263, BMS-345541, bortezomib (Velcade®), bryostatin 1, busulfan, carboplatin, campath-1H, CC-5103, carmustine, caspofungin acetate, clofarabine, cisplatin, Cladribine (Leustarin), Chlorambucil (Leukeran), Curcumin, cyclosporine, Cyclophosphamide (Cyloxan, Endoxan, Endoxana, Cyclostin), cytarabine, denileukin diftitox, dexamethasone, DT PACE
  • the cancer is melanoma.
  • Suitable agents for use in combination with the compounds described herein include, without limitation, dacarbazine (DTIC), optionally, along with other chemotherapy drugs such as carmustine (BCNU) and cisplatin; the "Dartmouth regimen", which consists of DTIC, BCNU, cisplatin and tamoxifen; a combination of cisplatin, vinblastine, and DTIC, temozolomide or YERVOYTM.
  • Compounds according to the invention may also be combined with immunotherapy drugs, including cytokines such as interferon alpha, interleukin 2, and tumor necrosis factor (TNF) in the treatment of melanoma.
  • cytokines such as interferon alpha, interleukin 2, and tumor necrosis factor (TNF)
  • Anti-melanoma vaccines are, in some ways, similar to the anti-virus vaccines which are used to prevent diseases caused by viruses such as polio, measles, and mumps.
  • Weakened melanoma cells or parts of melanoma cells called antigens may be injected into a patient to stimulate the body's immune system to destroy melanoma cells.
  • Melanomas that are confined to the arms or legs may also be treated with a combination of agents including one or more compounds described herein, using a hyperthermic isolated limb perfusion technique.
  • This treatment protocol temporarily separates the circulation of the involved limb from the rest of the body and injects high doses of chemotherapy into the artery feeding the limb, thus providing high doses to the area of the tumor without exposing internal organs to these doses that might otherwise cause severe side effects.
  • the fluid is warmed to 102° to 104° F.
  • Melphalan is the drug most often used in this chemotherapy procedure. This can be given with another agent called tumor necrosis factor (TNF).
  • TNF tumor necrosis factor
  • the therapeutic treatments can be supplemented or combined with any of the abovementioned therapies with stem cell transplantation or treatment.
  • One example of modified approach is radioimmunotherapy, wherein a monoclonal antibody is combined with a radioisotope particle, such as indium In 111, yttrium Y 90, iodine 1-131.
  • combination therapies include, but are not limited to, Iodine-131 tositumomab (Bexxar®), Yttrium-90 ibritumomab tiuxetan (Zevalin®), Bexxar® with CHOP.
  • peripheral blood stem cell transplantation autologous hematopoietic stem cell transplantation, autologous bone marrow transplantation, antibody therapy, biological therapy, enzyme inhibitor therapy, total body irradiation, infusion of stem cells, bone marrow ablation with stem cell support, in vitro -treated peripheral blood stem cell transplantation, umbilical cord blood transplantation, immunoenzyme technique, pharmacological study, low-LET cobalt-60 gamma ray therapy, bleomycin, conventional surgery, radiation therapy, and nonmyeloablative allogeneic hematopoietic stem cell transplantation.
  • a compound of formula I for use in a method for treating or preventing an HBV infection in a human having or at risk of having the infection comprising administering to the human a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more (e.g., one, two, three, four, one or two, or one to three, or one to four) additional therapeutic agents.
  • a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of one or more (e.g., one, two, three, four, one or two, or one to three, or one to four) additional therapeutic agents.
  • a compound of formula I for use in a method for treating an HBV infection in a human having or at risk of having the infection comprising administering to the human a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more (e.g., one, two, three, four, one or two, or one to three, or one to four) additional therapeutic agents.
  • a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of one or more (e.g., one, two, three, four, one or two, or one to three, or one to four) additional therapeutic agents.
  • the present disclosure provides a compound of formula I for use in a method for treating an HBV infection, comprising administering to a patient in need thereof a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more additional therapeutic agents which are suitable for treating an HBV infection.
  • compositions comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with one or more (e.g., one, two, three, four, one or two, or one to three, or one to four) additional therapeutic agents, and a pharmaceutically acceptable carrier, diluent or excipient are provided.
  • kits comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with one or more (e.g., one, two, three, four, one or two, or one to three, or one to four) additional therapeutic agents are provided.
  • the additional therapeutic agent may be an anti-HBV agent.
  • the additional therapeutic agent is selected from the group consisting of HBV combination drugs, HBV DNA polymerase inhibitors, immunomodulators, toll-like receptor modulators (modulators of tlr1, tlr2, tlr3, tlr4, tlr5, tlr6, tlr7, tlr8, tlr9, tlr10, tlr11, tlr12 and tlr13), interferon alpha receptor ligands, hyaluronidase inhibitors, recombinant IL-7, hepatitis B surface antigen (HBsAg) inhibitors, compounds targeting hepatitis B core antigen (HbcAg), cyclophilin inhibitors , HBV therapeutic vaccines, HBV prophylactic vaccines, HBV viral entry inhibitors, NTCP (Na+-taurocholate cotransporting polypeptide)
  • the additional therapeutic is selected from the group consisting of HBV combination drugs, HBV DNA polymerase inhibitors, toll-like receptor 7 modulators, toll-like receptor 8 modulators, Toll-like receptor 7 and 8 modulators, Toll-like receptor 3 modulators, interferon alpha receptor ligands, HBsAg inhibitors, compounds targeting HbcAg, cyclophilin inhibitors, HBV therapeutic vaccines, HBV prophylactic vaccines, HBV viral entry inhibitors, NTCP inhibitors, antisense oligonucleotide targeting viral mRNA, short interfering RNAs (siRNA), hepatitis B virus E antigen inhibitors, HBx inhibitors, cccDNA inhibitors, HBV antibodies including HBV antibodies targeting the surface antigens of the hepatitis B virus, thymosin agonists, cytokines, nucleoprotein inhibitors (HBV core or capsid protein inhibitors), stimulators of retinoic acid-inducible gene 1, stimul
  • a compound disclosed herein is formulated as a tablet, which may optionally contain one or more other compounds useful for treating HBV.
  • the tablet can contain another active ingredient for treating HBV, such as HBV DNA polymerase inhibitors, immunomodulators, toll-like receptor modulators (modulators of tlr1, tlr2, tlr3, tlr4, tlr5, tlr6, tlr7, tlr8, tlr9, tlr10, tlr11, tlr12 and tlr13), modulators of tlr7, modulators of tlr8, modulators of tlr7 and tlr8, interferon alpha receptor ligands, hyaluronidase inhibitors, hepatitis B surface antigen (HBsAg) inhibitors, compounds targeting hepatitis B core antigen (HbcAg), cyclophilin inhibitors , HBV viral entry inhibitors, NTCP
  • such tablets are suitable for once daily dosing.
  • the additional therapeutic agent is selected from one or more of:
  • a compound disclosed herein, or a pharmaceutically acceptable salt thereof is combined with one, two, three, four or more additional therapeutic agents. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with two additional therapeutic agents. In other embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with three additional therapeutic agents. In further embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with four additional therapeutic agents.
  • the one, two, three, four or more additional therapeutic agents can be different therapeutic agents selected from the same class of therapeutic agents, and/or they can be selected from different classes of therapeutic agents.
  • a compound disclosed herein, or a pharmaceutically acceptable salt thereof is combined with an HBV DNA polymerase inhibitor.
  • a compound disclosed herein, or a pharmaceutically acceptable salt thereof is combined with an HBV DNA polymerase inhibitor and at least one additional therapeutic agent selected from the group consisting of: immunomodulators, toll-like receptor modulators (modulators of tlr1, tlr2, tlr3, tlr4, tlr5, tlr6, tlr7, tlr8, tlr9, tlr10, tlr11, tlr12 and tlr13), interferon alpha receptor ligands, hyaluronidase inhibitors, recombinant IL-7, HBsAg inhibitors, compounds targeting HbcAg, cyclophilin inhibitors , HBV therapeutic vaccines, HBV prophylactic vaccines HBV viral entry inhibitors, NTCP inhibitors, antisense oligonu
  • a compound disclosed herein, or a pharmaceutically acceptable salt thereof is combined with an HBV DNA polymerase inhibitor and at least a second additional therapeutic agent selected from the group consisting of: immunomodulators, toll-like receptor modulators (modulators of tlr1, tlr2, tlr3, tlr4, tlr5, tlr6, tlr7, tlr8, tlr9, tlr10, tlr11, tlr12 and tlr13), HBsAg inhibitors, HBV therapeutic vaccines, HBV antibodies including HBV antibodies targeting the surface antigens of the hepatitis B virus and bispecific antibodies and "antibody-like" therapeutic proteins (such as DARTs®, Duobodies®, Bites®, XmAbs®, TandAbs ®, Fab derivatives), cyclophilin inhibitors, stimulators of retinoic acid-inducible gene 1, PD-1 inhibitors, PD-L1 inhibitors
  • a compound disclosed herein, or a pharmaceutically acceptable salt thereof is combined with an HBV DNA polymerase inhibitor and at least a second additional therapeutic agent selected from the group consisting of: HBV viral entry inhibitors, NTCP inhibitors, HBx inhibitors, cccDNA inhibitors, HBV antibodies targeting the surface antigens of the hepatitis B virus, short interfering RNAs (siRNA), miRNA gene therapy agents, short synthetic hairpin RNAs (sshRNAs), and nucleoprotein inhibitors (HBV core or capsid protein inhibitors).
  • a second additional therapeutic agent selected from the group consisting of: HBV viral entry inhibitors, NTCP inhibitors, HBx inhibitors, cccDNA inhibitors, HBV antibodies targeting the surface antigens of the hepatitis B virus, short interfering RNAs (siRNA), miRNA gene therapy agents, short synthetic hairpin RNAs (sshRNAs), and nucleoprotein inhibitors (HBV core or capsid protein inhibitors).
  • a compound disclosed herein, or a pharmaceutically acceptable salt thereof is combined with an HBV DNA polymerase inhibitor, one or two additional therapeutic agents selected from the group consisting of: immunomodulators, toll-like receptor modulators (modulators of tlr1, tlr2, tlr3, tlr4, tlr5, tlr6, tlr7, tlr8, tlr9, tlr10, tlr11, tlr12 and tlr13), HBsAg inhibitors, HBV therapeutic vaccines, HBV antibodies including HBV antibodies targeting the surface antigens of the hepatitis B virus and bispecific antibodies and "antibody-like" therapeutic proteins (such as DARTs®, Duobodies®, Bites®, XmAbs®, TandAbs ®, Fab derivatives), cyclophilin inhibitors, stimulators of retinoic acid-inducible gene 1, PD-1 inhibitors, PD-L1 inhibitors, Ar
  • a compound disclosed herein, or a pharmaceutically acceptable salt thereof is combined with one, two, three, four or more additional therapeutic agents selected from adefovir (Hepsera®), tenofovir disoproxil fumarate + emtricitabine (TRUVADA®), tenofovir disoproxil fumarate (Viread®), entecavir (Baraclude®), lamivudine (Epivir-HBV®), tenofovir alafenamide, tenofovir, tenofovir disoproxil, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, telbivudine (Tyzeka®), Clevudine®, emtricitabine (Emtriva®), peginterferon alfa-2b (PEG-Intron®), Multiferon®, interferon alpha 1b (Hapgen®), inter
  • a compound disclosed herein, or a pharmaceutically acceptable salt thereof is combined with entecavir (Baraclude®), adefovir (Hepsera®), tenofovir disoproxil fumarate (Viread®), tenofovir alafenamide, tenofovir, tenofovir disoproxil, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, telbivudine (Tyzeka®) or lamivudine (Epivir-HBV®).
  • a compound disclosed herein, or a pharmaceutically acceptable salt thereof is combined with entecavir (Baraclude®), adefovir (Hepsera®), tenofovir disoproxil fumarate (Viread®), tenofovir alafenamide hemifumarate, telbivudine (Tyzeka®) or lamivudine (Epivir-HBV®).
  • a compound disclosed herein, or a pharmaceutically acceptable salt thereof is combined with a first additional therapeutic agent selected from the group consisting of: entecavir (Baraclude®), adefovir (Hepsera®), tenofovir disoproxil fumarate (Viread®), tenofovir alafenamide, tenofovir, tenofovir disoproxil, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, telbivudine (Tyzeka®) or lamivudine (Epivir-HBV®) and at least a second additional therapeutic agent selected from the group consisting of immunomodulators, toll-like receptor modulators (modulators of tlr1, tlr2, tlr3, tlr4, tlr5, tlr6, tlr7, tlr8, tlr9, tlr10,
  • a compound disclosed herein, or a pharmaceutically acceptable salt thereof is combined with a first additional therapeutic agent selected from the group consisting of: entecavir (Baraclude®), adefovir (Hepsera®), tenofovir disoproxil fumarate (Viread®), tenofovir alafenamide, tenofovir, tenofovir disoproxil, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, telbivudine (Tyzeka®) or lamivudine (Epivir-HBV®) and at least a second additional therapeutic agent selected from the group consisting of peginterferon alfa-2b (PEG-Intron®), Multiferon®, interferon alpha 1b (Hapgen®), interferon alpha-2b (Intron A®), pegylated interferon alpha-2a (Pegasys
  • a compound disclosed herein, or a pharmaceutically acceptable salt thereof is combined with a first additional therapeutic agent selected from the group consisting of: entecavir (Baraclude®), adefovir (Hepsera®), tenofovir disoproxil fumarate (Viread®), tenofovir alafenamide, tenofovir, tenofovir disoproxil, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, telbivudine (Tyzeka®) or lamivudine (Epivir-HBV®) and at least a second additional therapeutic agent selected from the group consisting of immunomodulators, toll-like receptor modulators (modulators of tlr1, tlr2, tlr3, tlr4, tlr5, tlr6, tlr7, tlr8, tlr9, tlr10,
  • a compound disclosed herein, or a pharmaceutically acceptable salt thereof is combined with a first additional therapeutic agent selected from the group consisting of: entecavir (Baraclude®), adefovir (Hepsera®), tenofovir disoproxil fumarate (Viread®), tenofovir alafenamide, tenofovir, tenofovir disoproxil, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, telbivudine (Tyzeka®) or lamivudine (Epivir-HBV®) and at least a second additional therapeutic agent selected from the group consisting of HBV viral entry inhibitors, NTCP inhibitors, HBx inhibitors, cccDNA inhibitors, HBV antibodies targeting the surface antigens of the hepatitis B virus, short interfering RNAs (siRNA), miRNA gene therapy agents, short synthetic hairpin
  • a compound disclosed herein, or a pharmaceutically acceptable salt thereof is combined with a first additional therapeutic agent selected from the group consisting of: entecavir (Baraclude®), adefovir (Hepsera®), tenofovir disoproxil fumarate (Viread®), tenofovir alafenamide, tenofovir, tenofovir disoproxil, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, telbivudine (Tyzeka®) or lamivudine (Epivir-HBV®), one or two additional therapeutic agents selected from the group consisting of: immunomodulators, toll-like receptor modulators (modulators of tlr1, tlr2, tlr3, tlr4, tlr5, tlr6, tlr7, tlr8, tlr9, tlr10, t
  • a compound disclosed herein, or a pharmaceutically acceptable salt thereof is combined with 5-30 mg tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 5-10; 5-15; 5-20; 5-25; 25-30; 20-30; 15-30; or 10-30 mg tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide.
  • a compound disclosed herein, or a pharmaceutically acceptable salt thereof is combined with 10 mg tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 25 mg tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide.
  • a compound as disclosed herein may be combined with the agents provided herein in any dosage amount of the compound (e.g., from 50 mg to 500 mg of compound) the same as if each combination of dosages were specifically and individually listed.
  • a compound disclosed herein, or a pharmaceutically acceptable salt thereof is combined with 100-400 mg tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil.
  • a compound disclosed herein, or a pharmaceutically acceptable salt thereof is combined with 100-150; 100-200, 100-250; 100-300; 100-350; 150-200; 150-250; 150-300; 150-350; 150-400; 200-250; 200-300; 200-350; 200-400; 250-350; 250-400; 350-400 or 300-400 mg tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil.
  • a compound disclosed herein, or a pharmaceutically acceptable salt thereof is combined with 300 mg tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 250 mg tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil.
  • a compound disclosed herein, or a pharmaceutically acceptable salt thereof is combined with 150 mg tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil.
  • a compound as disclosed herein e.g., a compound of formula (I)
  • the components of the composition are administered as a simultaneous or sequential regimen.
  • the combination may be administered in two or more administrations.
  • a compound disclosed herein is combined with one or more additional therapeutic agents in a unitary dosage form for simultaneous administration to a patient, for example as a solid dosage form for oral administration.
  • a compound disclosed herein is administered with one or more additional therapeutic agents.
  • Co-administration of a compound disclosed herein with one or more additional therapeutic agents generally refers to simultaneous or sequential administration of a compound disclosed herein and one or more additional therapeutic agents, such that therapeutically effective amounts of the compound disclosed herein and one or more additional therapeutic agents are both present in the body of the patient.
  • Co-administration includes administration of unit dosages of the compounds disclosed herein before or after administration of unit dosages of one or more additional therapeutic agents, for example, administration of the compound disclosed herein within seconds, minutes, or hours of the administration of one or more additional therapeutic agents.
  • a unit dose of a compound disclosed herein is administered first, followed within seconds or minutes by administration of a unit dose of one or more additional therapeutic agents.
  • a unit dose of one or more additional therapeutic agents is administered first, followed by administration of a unit dose of a compound disclosed herein within seconds or minutes.
  • a unit dose of a compound disclosed herein is administered first, followed, after a period of hours (e.g., 1-12 hours), by administration of a unit dose of one or more additional therapeutic agents.
  • a unit dose of one or more additional therapeutic agents is administered first, followed, after a period of hours (e.g., 1-12 hours), by administration of a unit dose of a compound disclosed herein.
  • a compound of formula I for use in a method for treating or preventing an HIV infection in a human having or at risk of having the infection comprising administering to the human a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more (e.g., one, two, three, four, one or two, or one to three, or one to four) additional therapeutic agents.
  • a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of one or more (e.g., one, two, three, four, one or two, or one to three, or one to four) additional therapeutic agents.
  • a compound of formula I for use in a method for treating an HIV infection in a human having or at risk of having the infection comprising administering to the human a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more (e.g., one, two, three, four, one or two, or one to three, or one to four) additional therapeutic agents.
  • a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of one or more (e.g., one, two, three, four, one or two, or one to three, or one to four) additional therapeutic agents.
  • the present disclosure provides a compound of formula I for use in a method for treating an HIV infection, comprising administering to a patient in need thereof a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more additional therapeutic agents which are suitable for treating an HIV infection.
  • compositions comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with one or more (e.g., one, two, three, four, one or two, or one to three, or one to four) additional therapeutic agents, and a pharmaceutically acceptable carrier, diluent or excipient are provided.
  • kits comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with one or more (e.g., one, two, three, four, one or two, or one to three, or one to four) additional therapeutic agents are provided.
  • the additional therapeutic agent may be an anti- HIV agent.
  • the additional therapeutic agent is selected from the group consisting of HIV protease inhibitors, HIV non-nucleoside inhibitors of reverse transcriptase, HIV nucleoside or nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, entry inhibitors (e.g., CCR5 inhibitors, gp41 inhibitors (i.e., fusion inhibitors) and CD4 attachment inhibitors), CXCR4 inhibitors, gpl20 inhibitors, G6PD and NADH-oxidase inhibitors, compounds that target the HIV capsid ("capsid inhibitors"; e.g., capsid polymerization inhibitors or capsid disrupting compounds such as those disclosed in WO 2013/006738 (Gilead Sciences), US 2013/0165489 (University of Pennsylvania), and WO
  • the additional therapeutic agent is selected from one or more of:
  • the additional therapeutic agent is a Toll-like receptor 8 modulator selected from the group consisting of motolimod, resiquimod, 3M-051, 3M-052, MCT-465, IMO-4200, VTX-763, VTX-1463 and those disclosed in US20140045849 (Janssen), US20140073642 (Janssen), WO2014/056953 (Janssen), WO2014/076221 (Janssen), WO2014/128189 (Janssen), US20140350031 (Janssen), WO2014/023813 (Janssen), US20080234251 (Array Biopharma), US20080306050 (Array Biopharma), US20100029585 (Ventirx Pharma), US20110092485 (Ventirx Pharma), US20110118235 (Ventirx Pharma), US20120082658 (Ventirx Pharma),
  • a compound disclosed herein, or a pharmaceutically acceptable salt thereof is combined with one, two, three, four or more additional therapeutic agents. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with two additional therapeutic agents. In other embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with three additional therapeutic agents. In further embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with four additional therapeutic agents.
  • the two, three, four or more additional therapeutic agents can be different therapeutic agents selected from the same class of therapeutic agents, or they can be selected from different classes of therapeutic agents.
  • a compound disclosed herein, or a pharmaceutically acceptable salt thereof is combined with an HIV nucleoside or nucleotide inhibitor of reverse transcriptase and an HIV non-nucleoside inhibitor of reverse transcriptase.
  • a compound disclosed herein, or a pharmaceutically acceptable salt thereof is combined with an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, and an HIV protease inhibiting compound.
  • a compound disclosed herein, or a pharmaceutically acceptable salt thereof is combined with an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, an HIV non-nucleoside inhibitor of reverse transcriptase, and an HIV protease inhibiting compound.
  • a compound disclosed herein, or a pharmaceutically acceptable salt thereof is combined with an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, an HIV non-nucleoside inhibitor of reverse transcriptase, and a pharmacokinetic enhancer.
  • a compound disclosed herein, or a pharmaceutically acceptable salt thereof is combined with two HIV nucleoside or nucleotide inhibitor of reverse transcriptase.
  • a compound disclosed herein, or a pharmaceutically acceptable salt thereof is combined with abacavir sulfate, tenofovir, tenofovir disoproxil fumarate, tenofovir alafenamide, or tenofovir alafenamide hemifumarate.
  • a compound disclosed herein, or a pharmaceutically acceptable salt thereof is combined with tenofovir, tenofovir disoproxil fumarate, tenofovir alafenamide, or tenofovir alafenamide hemifumarate.
  • a compound disclosed herein, or a pharmaceutically acceptable salt thereof is combined with a first additional therapeutic agent selected from the group consisting of: abacavir sulfate, tenofovir, tenofovir disoproxil fumarate, tenofovir alafenamide, and tenofovir alafenamide hemifumarate and a second additional therapeutic agent selected from the group consisting of emtricitibine and lamivudine.
  • a first additional therapeutic agent selected from the group consisting of: abacavir sulfate, tenofovir, tenofovir disoproxil fumarate, tenofovir alafenamide, and tenofovir alafenamide hemifumarate
  • a second additional therapeutic agent selected from the group consisting of emtricitibine and lamivudine.
  • a compound disclosed herein, or a pharmaceutically acceptable salt thereof is combined with a first additional therapeutic agent selected from the group consisting of: tenofovir, tenofovir disoproxil fumarate, tenofovir alafenamide, and tenofovir alafenamide hemifumarate and a second additional therapeutic agent, wherein the second additional therapeutic agent is emtricitibine.
  • the components of the composition are administered as a simultaneous or sequential regimen.
  • the combination may be administered in two or more administrations.
  • a compound disclosed herein is combined with one or more additional therapeutic agents in a unitary dosage form for simultaneous administration to a patient, for example as a solid dosage form for oral administration.
  • a compound disclosed herein is administered with one or more additional therapeutic agents.
  • Co-administration of a compound disclosed herein with one or more additional therapeutic agents generally refers to simultaneous or sequential administration of a compound disclosed herein and one or more additional therapeutic agents, such that therapeutically effective amounts of the compound disclosed herein and one or more additional therapeutic agents are both present in the body of the patient.
  • Co-administration includes administration of unit dosages of the compounds disclosed herein before or after administration of unit dosages of one or more additional therapeutic agents, for example, administration of the compound disclosed herein within seconds, minutes, or hours of the administration of one or more additional therapeutic agents.
  • a unit dose of a compound disclosed herein is administered first, followed within seconds or minutes by administration of a unit dose of one or more additional therapeutic agents.
  • a unit dose of one or more additional therapeutic agents is administered first, followed by administration of a unit dose of a compound disclosed herein within seconds or minutes.
  • a unit dose of a compound disclosed herein is administered first, followed, after a period of hours (e.g., 1-12 hours), by administration of a unit dose of one or more additional therapeutic agents.
  • a unit dose of one or more additional therapeutic agents is administered first, followed, after a period of hours (e.g., 1-12 hours), by administration of a unit dose of a compound disclosed herein.
  • kits that include a compound of Formula I, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, and suitable packaging.
  • a kit further includes instructions for use.
  • a kit includes a compound of Formula I, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, and a label and/or instructions for use of the compounds in the treatment of the indications, including the diseases or conditions, described herein.
  • articles of manufacture that include a compound described herein or pharmaceutically acceptable salts, or a mixture thereof in a suitable container.
  • the container may be a vial, jar, ampoule, preloaded syringe, and intravenous bag.
  • compositions that contain one or more of the compounds described herein or pharmaceutically acceptable salts, isomer, or a mixture thereof and one or more pharmaceutically acceptable vehicles selected from carriers, adjuvants and excipients.
  • Suitable pharmaceutically acceptable vehicles may include, for example, inert solid diluents and fillers, diluents, including sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers and adjuvants.
  • Such compositions are prepared in a manner well known in the pharmaceutical art. See, e.g ., Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa. 17th Ed. (1985 ); and Modern Pharmaceutics, Marcel Dekker, Inc. 3rd Ed. (G.S. Banker & C.T. Rhodes, Eds .).
  • the pharmaceutical compositions may be administered in either single or multiple doses.
  • the pharmaceutical composition may be administered by various methods including, for example, rectal, buccal, intranasal and transdermal routes.
  • the pharmaceutical composition may be administered by intraarterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, or as an inhalant.
  • Oral administration may be another route for administration of the compounds described herein. Administration may be via, for example, capsule or enteric coated tablets.
  • the active ingredient is usually diluted by an excipient and/or enclosed within such a carrier that can be in the form of a capsule, sachet, paper or other container.
  • the excipient serves as a diluent, it can be in the form of a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient.
  • compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injectable solutions, and sterile packaged powders.
  • excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methyl cellulose.
  • the formulations can additionally include lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl and propylhydroxy-benzoates; sweetening agents; and flavoring agents.
  • compositions that include at least one compound described herein or pharmaceutically acceptable salts, or a mixture thereof can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the subject by employing procedures known in the art.
  • Controlled release drug delivery systems for oral administration include osmotic pump systems and dissolutional systems containing polymer-coated reservoirs or drug-polymer matrix formulations. Examples of controlled release systems are given in U.S. Patent Nos. 3,845,770 ; 4,326,525 ; 4,902,514 ; and 5,616,345 .
  • Another formulation for use in the methods of the present invention employs transdermal delivery devices ("patches"). Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds described herein in controlled amounts.
  • transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, e.g. , U.S. Patent Nos. 5,023,252 , 4,992,445 and 5,001,139 . Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.
  • the principal active ingredient may be mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound described herein or pharmaceutically acceptable salts, or a mixture thereof.
  • a pharmaceutical excipient When referring to these preformulation compositions as homogeneous, the active ingredient may be dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.
  • the tablets or pills of the compounds described herein may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action, or to protect from the acid conditions of the stomach.
  • the tablet or pill can include an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
  • the two components can be separated by an enteric layer that serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release.
  • enteric layers or coatings such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.
  • compositions for inhalation or insufflation may include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders.
  • the liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra.
  • the compositions are administered by the oral or nasal respiratory route for local or systemic effect.
  • compositions in pharmaceutically acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be inhaled directly from the nebulizing device or the nebulizing device may be attached to a facemask tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from devices that deliver the formulation in an appropriate manner.
  • a dosage may be expressed as a number of milligrams of a compound described herein per kilogram of the subject's body weight (mg/kg). Dosages of between about 0.1 and 150 mg/kg may be appropriate. In some embodiments, about 0.1 and 100 mg/kg may be appropriate. In other embodiments a dosage of between 0.5 and 60 mg/kg may be appropriate.
  • Normalizing according to the subject's body weight is particularly useful when adjusting dosages between subjects of widely disparate size, such as occurs when using the drug in both children and adult humans or when converting an effective dosage in a non-human subject such as dog to a dosage suitable for a human subject.
  • the daily dosage may also be described as a total amount of a compound described herein administered per dose or per day.
  • Daily dosage of a compound of Formula I may be between about 1 mg and 4,000 mg, between about 2,000 to 4,000 mg/day, between about 1 to 2,000 mg/day, between about 1 to 1,000 mg/day, between about 10 to 500 mg/day, between about 20 to 500 mg/day, between about 50 to 300 mg/day, between about 75 to 200 mg/day, or between about 15 to 150 mg/day.
  • the total daily dosage for a human subject may be between 1 mg and 1,000 mg, between about 10-500 mg/day, between about 50-300 mg/day, between about 75-200 mg/day, or between about 100-150 mg/day.
  • the compounds of the present application or the compositions thereof may be administered once, twice, three, or four times daily, using any suitable mode described above. Also, administration or treatment with the compounds may be continued for a number of days; for example, commonly treatment would continue for at least 7 days, 14 days, or 28 days, for one cycle of treatment. Treatment cycles are well known in cancer chemotherapy, and are frequently alternated with resting periods of about 1 to 28 days, commonly about 7 days or about 14 days, between cycles. The treatment cycles, in other embodiments, may also be continuous.
  • the method comprises administering to the subject an initial daily dose of about 1 to 500 mg of a compound described herein and increasing the dose by increments until clinical efficacy is achieved. Increments of about 5, 10, 25, 50, or 100 mg can be used to increase the dose. The dosage can be increased daily, every other day, twice per week, or once per week.
  • the compounds may be prepared using the methods disclosed herein and routine modifications thereof, which will be apparent given the disclosure herein and methods well known in the art. Conventional and well-known synthetic methods may be used in addition to the teachings herein. The synthesis of typical compounds described herein may be accomplished as described in the following examples. If available, reagents may be purchased commercially, e.g., from Sigma Aldrich or other chemical suppliers.
  • Typical embodiments of compounds described herein may be synthesized using the general reaction schemes described below. It will be apparent given the description herein that the general schemes may be altered by substitution of the starting materials with other materials having similar structures to result in products that are correspondingly different. Descriptions of syntheses follow to provide numerous examples of how the starting materials may vary to provide corresponding products. Given a desired product for which the substituent groups are defined, the necessary starting materials generally may be determined by inspection. Starting materials are typically obtained from commercial sources or synthesized using published methods. For synthesizing compounds which are embodiments described in the present disclosure, inspection of the structure of the compound to be synthesized will provide the identity of each substituent group. The identity of the final product will generally render apparent the identity of the necessary starting materials by a simple process of inspection, given the examples herein. In general, compounds described herein are typically stable and isolatable at room temperature and pressure.
  • the compounds of this disclosure can be prepared from readily available starting materials using, for example, the following general methods and procedures. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures.
  • protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions.
  • Suitable protecting groups for various functional groups as well as suitable conditions for protecting and deprotecting particular functional groups are well known in the art. For example, numerous protecting groups are described in T. W. Greene and G. M. Wuts (1999) Protecting Groups in Organic Synthesis, 3rd Edition, Wiley, New York , and references cited therein.
  • the compounds of this disclosure may contain one or more chiral centers. Accordingly, if desired, such compounds can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereomers or as stereoisomer-enriched mixtures. All such stereoisomers (and enriched mixtures) are included within the scope of this disclosure, unless otherwise indicated. Pure stereoisomers (or enriched mixtures) may be prepared using, for example, optically active starting materials or stereoselective reagents well-known in the art. Alternatively, racemic mixtures of such compounds can be separated using, for example, chiral column chromatography, chiral resolving agents, and the like.
  • the starting materials for the following reactions are generally known compounds or can be prepared by known procedures or obvious modifications thereof.
  • many of the starting materials are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA), Bachem (Torrance, California, USA), Emka-Chemce or Sigma (St. Louis, Missouri, USA).
  • solvent refers to a solvent inert under the conditions of the reaction being described in conjunction therewith (including, for example, benzene, toluene, acetonitrile, tetrahydrofuran (“THF”), dimethylformamide (“DMF”), chloroform, methylene chloride (or dichloromethane), diethyl ether, methanol, and the like).
  • solvents used in the reactions of the present invention are inert organic solvents, and the reactions are carried out under an inert gas, preferably nitrogen.
  • q.s means adding a quantity sufficient to achieve a stated function, e.g. , to bring a solution to the desired volume (i.e. , 100%).
  • the compounds of Formula I may prepared by first providing the substituted imidazo[4,5-b]pyridine or benzimidazole core, and optionally further modifying the core as desired to provide the substituents disclosed herein.
  • Scheme 1 shows the preparation of compounds of Formula I, where m, n, L, R 1 , R 2a , R 2b , and X are as defined herein, and R 4 is as defined herein, or a functional group that is converted thereto using standard reaction conditions and protection/deprotection steps as required.
  • Suitable solvent e.g., formic acid, ethanol, etc.
  • an elevated temperature typically about 80-100 °C
  • 1-c is then converted to the corresponding thioamide 1-d using Lawesson's reagent (i.e., 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulfide) under standard conditions.
  • 1-e is obtained by cyclization of the thioamide 1-d using hydroxylamine.
  • Scheme 2 shows the synthesis of compounds of Formula I where R t is hydrogen, and R 1 , R 2a , R 2b , and X are as defined herein.
  • 2-a is nitrated using fuming nitric acid to provide 2-b , which is then cyclized to provide C-2 unsubstituted imidazo[4,5-b]pyridine or benzimidazole 2-c under reducing conditions (e.g., zinc, iron, etc.).
  • Amide 2-e is provided by reacting the corresponding ester 2-c with a suitable amine 2-d under standard amide bond forming reaction conditions, and is then converted to compounds of Formula I using the methods shown above in Scheme 1.
  • Scheme 3 shows the synthesis of compounds of Formula I where R t is - NH 2 , and R 1 , R 2a , R 2b , and X are as defined herein.
  • 3-b is obtained by reaction of 3-a with cyanogen bromide.
  • Amide 3-d is provided by reacting the corresponding ester 3-b with a suitable amine 3-c under standard amide bond forming reaction conditions, and is then converted to compounds of Formula I using the methods shown above in Scheme 1.
  • the process may comprise protection and deprotection/further modification of R 4 (Scheme 1) to provide the desired group in the compound of Formula I.
  • Scheme 4 shows an exemplary protection/deprotection or further modification to provide compounds of Formula I, where R t , R m , m, L, R 1 , R 2a , R 2b , and X are as defined herein.
  • suitably substituted 4-a can be protected to provide 4-b using a suitable proecting group PG, such as a silyl ether (see, e.g., T. W. Greene and G. M. Wuts (1999) Protecting Groups in Organic Synthesis, 3rd Edition, Wiley, New York , and references cited therein).
  • PG a suitable proecting group
  • 4-b is then converted to the corresponding thioamide 4-c and cyclized using hydroxylamine as shown above in Scheme 1 to provide 4-d .
  • 4-d can then be coverted to compound 4-e by deprotectiona and optional further modification.
  • 4-d can be deprotected and converted to a suitable leaving group (e.g., a TMS-O- group) and then reacted with a suitable amine to provide compounds of formula 4-e where L is -NR 3 -. 4-e is then converted to compounds of Formula I using the methods shown above in Scheme 1.
  • a suitable leaving group e.g., a TMS-O- group
  • 4-e is then converted to compounds of Formula I using the methods shown above in Scheme 1.
  • TFA Trifluoroacetic acid
  • THF Tetrahydrofuran TIGIT
  • T cell immunoreceptor with Ig and ITIM domains TIM T-cell immunoglobulin and mucin domain
  • TKM-HBV TKM-HepB
  • Tlr Toll-like receptor modulators TNF Tumor necrosis factor
  • TPL2 Serine/threonine kinase Vac Vacuum w/v Weight/volume w/w Weight/weight YPEG-rhIFNalpha-2a PEG-interferon alfa-2a YPEG-rhIFNalpha-2b Ypeginterferon alfa-2b ⁇ Chemical shift (ppm) ⁇ g Microgram ⁇ L/ ⁇ l Microliter ⁇ M Micromolar ⁇ m Micrometer ⁇ mol Micromole
  • Methyl 3-formamido-4-methyl-2-nitrobenzoate Methyl 3-formamido-4-methylbenzoate (5.3 g, 27 mmol) was added to fuming nitric acid at 0 °C portion wise over 45 min. The reaction mixture was stirred at 0 °C for an additional 1 h, and then ice was added and the mixture stirred for 1.5 h at room temperature. The precipitated solid was filtered, and washed with water. The solid was purified by silica gel to give the desired product. C 10 H 10 N 2 O 5 . 239.0 (M+1).
  • Methyl 4-methyl-1H-benzo[d]imidazole-7-carboxylate A mixture of methyl 3-formamido-4-methyl-2-nitrobenzoate (1.0 g, 4.2 mmol) and iron (1.2 g, 21 mmol) in methanol (10 mL) and acetic acid (5 mL) was stirred at 70 °C for 3 hr. To the cooled reaction mixture was added ethyl acetate and water and the mixture was filtered and the solid was washed with ethyl acetate. The aqueous layer was washed two times with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated to give the desired product. C 10 H 10 N 2 O 2 . 191.1 (M+1).
  • N-(3-chloro-4-fluorophenyl)-4-methyl-1H-benzo[d]imidazole-7-carboxamide N-(3-chloro-4-fluorophenyl)-4-methyl-1H-benzo[d]imidazole-7-carboxamide.
  • 3-chloro-4-fluoroanilinein 253 mg, 1.74 mmol
  • dichloroethane at 0 °C under nitrogen was added trimethylaluminum (2 M in heptane, 1.74 mL, 3.47 mmol) dropwise over 5 min.
  • the solution was allowed to warm to room temperature and stirred for 30 min.
  • the solution was cooled to 0 °C and to this solution was added methyl 4-methyl-1H-benzo[d]imidazole-7-carboxylate (220 mg, 1.16 mmol).
  • N-(3-chloro-4-fluorophenyl)-N'-hydroxy-4-methyl-1H-benzo[d]imidazole-7-carboximidamide A mixture of N-(3-chloro-4-fluorophenyl)-4-methyl-1H-benzo[d]imidazole-7-carboxamide (154 mg, 0.507 mmol), phosphorous pentachloride (158 mg, 0.761 mmol) in phosphoryl chloride (1.5 mL) and 1,2-dichloroethane (1.5 mL) were stirred at 80 °C for 2.5 hr.
  • Methyl 2-formamido-3-nitro-4-(trifluoromethoxy)benzoate (2.2 g, 7.0 mmol) was dissolved in ethanol (15 mL) and water (5 mL). Ammonium chloride (0.108 mol) was added in one portion and the reaction was allowed to stir at room temperature. Zinc powder (0.108 mol) was added portion-wise over 5 minutes and the reaction was allowed to stir 5 minutes after completion of addition. The zinc was then removed by vacuum filtration and the filtrate was concentrated in vacuo. The crude was dissolved in water (20 mL) and extracted with EtOAc (4 x 10 mL). Combined organic layers were washed with brine (1 x 50 mL), dried over sodium sulfate, and concentrated in vacuo to give methyl 3-amino-2-formamido-4-(trifluoromethoxy)benzoate.
  • Methyl 3-amino-2-formamido-4-(trifluoromethoxy)benzoate (1.32 g, 5.0 mmol) was dissolved in formic acid (15 mL) and heated to 80 °C for 1 hour. The reaction was cooled to rt, concentrated in vacuo, and quenched with saturated sodium bicarbonate solution (10 mL). The mixture was extracted with EtOAc (4x5 mL) and combined organic layers were washed with brine (1x15 mL) and concentrated in vacuo. Crude material was purified by column chromatography to give methyl 4-(trifluoromethoxy)-1H-benzo[d]imidazole-7-carboxylate.
  • Example 2 was made analogously to Example 10 using methyl 4-(trifluoromethoxy)-1H-benzo[d]imidazole-7-carboxylate in place of methyl 4,5-difluoro-1 H -benzo[d]imidazole-7-carboxylate.
  • Example 3 (N-(3-chloro-4-fluorophenyl)-6-fluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide) was made analogously to Example 59 using 6-fluoro-1H-benzo[d]imidazole-7-carboxylic acid in place of 1H-imidazo[4,5-b]pyridine-7-carboxylic acid.
  • Example 4 was made analogously to Example 59 using 5-fluoro-1H-benzo[d]imidazole-7-carboxylic in place of 1H-imidazo[4,5-b]pyridine-7-carboxylic acid.
  • Example 5 was made analogously to Example 59 using 4-fluoro-1H-benzo[d]imidazole-7-carboxylic acid in place of 1H-imidazo[4,5-b]pyridine-7-carboxylic acid.
  • Example 6 was made analogously to Example 59 using 4-chloro-1H-benzo[d]imidazole-7-carboxylic acid in place of 1H-imidazo[4,5-b]pyridine-7-carboxylic acid.
  • Example 7 was made analogously to Example 59 using 4-(trifluoromethyl)-1H-benzo[d]imidazole-7-carboxylic acid in place of 1H-imidazo[4,5-b]pyridine-7-carboxylic acid. C 15 H 9 ClF 4 N 4 O. 373.1 (M+1).
  • Example 8 was made analogously to Example 59 using 1H-benzo[d]imidazole-7-carboxylic acid in place of 1H-imidazo[4,5-b]pyridine-7-carboxylic acid. C 14 H 10 ClFN 4 O. 305.1 (M+1).
  • N-(3-chloro-4-fluorophenyl)-5-fluoro-4-methyl-1H-benzo[d]imidazole-7-carboxamide was made analogously to Example 1 using N-(3-chloro-4-fluorophenyl)-5-fluoro-3-formamido-4-methyl-2-nitrobenzamide in place of methyl 3-formamido-4-methyl-2-nitrobenzoate.
  • N-(3-Chloro-4-fluorophenyl)-6-fluoro-N'-hydroxy-7-methyl-3H-benzimidazole-4-carboximidamide was made analogously to Example 1 using N-(3-chloro-4-fluorophenyl)-5-fluoro-4-methyl-1H-benzo[d]imidazole-7-carboxamide in place of N-(3-chloro-4-fluorophenyl)-4-methyl-1H-benzo[d]imidazole-7-carboxamide.
  • Methyl 2,3-diamino-4,5-difluorobenzoate (60 mg, 0.30 mmol) was dissolved in formic acid (2 mL) and heated to 100 °C in a sealed tube for 10 minutes. The reaction was allowed to cool to room temperature and concentrated in vacuo. The residue was dissolved in sat. sodium bicarbonate (2 mL) and extracted with EtOAc (3 x 3 mL). Combined organic layers were washed with water (1 x 5 mL) and concentrated in vacuo to give methyl 4,5-difluoro-1 H -benzo[d]imidazole-7-carboxylate as a brown solid which was used without further purification.
  • Methyl 4,5-difluoro-1 H -benzo[d]imidazole-7-carboxylate (12 mg, 0.056 mmol) was dissolved in DCE (1 mL) under an inert atmosphere. Trimethylaluminum (0.085 mL, 2.0 M in toluene) was added dropwise to the reaction followed by 3-chloro-4-fluoroaniline (0.085 mmol). The reaction was allowed to stir at rt overnight under inert atmosphere. The reaction was quenched with sat. sodium bicarb (3 mL) and extracted with EtOAc (3 x 2mL).
  • Methyl 5-chloro-3-formamido-2-nitrobenzoate was made analogously to Example 1 using methyl 3-amino-5-chloro-2-nitrobenzoate in place of methyl 3-amino-4-methylbenzoate.
  • Methyl 6-chloro-1H-benzo[d]imidazole-4-carboxylate was made analogously to Example 1 using methyl 5-chloro-3-formamido-2-nitrobenzoate in place of methyl 3-formamido-4-methyl-2-nitrobenzoate.
  • 6-chloro-N-(3-chloro-4-fluorophenyl)-1H-benzo[d]imidazole-4-carboxamide was made analogously to Example 1 using methyl 6-chloro-1H-benzo[d]imidazole-4-carboxylate in place of methyl 4-methyl-1H-benzo[d]imidazole-7-carboxylate.
  • 6-chloro-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-1H-benzo[d]imidazole-4-carboximidamide was made analogously to Example 1 using 6-chloro-N-(3-chloro-4-fluorophenyl)-1H-benzo[d]imidazole-4-carboxamide in place of N-(3-chloro-4-fluorophenyl)-4-methyl-1H-benzo[d]imidazole-7-carboxamide.
  • Methyl 4-bromo-3-formamidobenzoate was prepared analogously to Example 9, using methyl 3-amino-4-bromobenzoate in place of 3-amino- N -(3-chloro-4-fluorophenyl)-5-fluoro-4-methyl-2-nitrobenzamide.
  • Methyl 4-bromo-1 H -benzo[ d ]imidazole-7-carboxylate was prepared analogously to Example 1, using methyl 4-bromo-3-formamido-2-nitrobenzoate in place of methyl 3-formamido-4-methyl-2-nitrobenzoate.
  • Methyl 2-amino-4,5-difluoro-1 H -benzo[ d ]imidazole-7-carboxylate (75 mg, 0.33 mmol) was dissolved in DCE (4 mL) under inert atmosphere and cooled to 0 °C. Trimethylaluminium (1.2 mL, 2M hexanes) was added dropwise followed by 3-chloro-4-fluoroaniline (1.0 mmol) and the reaction was then heated to 70 °C for 2 days. The reaction was cooled to rt and quenched with saturated bicarbonate solution. The reaction was extracted with EtOAc (3x3 mL) and combined organic layers were washed with brine (1x6 mL) and concentrated in vacuo.
  • Example 14 was made analogously to Example 13 using 3-bromo-4-fluoroaniline in place of 3-chloro-4-fluoroaniline.
  • Example 15 was made analogously to Example 13 using 3-bromoaniline in place of 3-chloro-4-fluoroaniline.
  • Example 16 was made analogously to Example 13 using 3-chloroaniline in place of 3-chloro-4-fluoroaniline.
  • 1 H NMR (400 MHz, Methanol- d 4 ) ⁇ 8.69 - 8.59 (m, 2H), 8.51 - 8.45 (m, 1H), 8.39 (t, J 2.1 Hz, 1H), 8.21 - 8.15 (m, 1H).
  • Example 17 was made analogously to Example 13 using 4-fluoro-3-(trifluoromethyl)aniline in place of 3-chloro-4-fluoroaniline.
  • 1 H NMR (400 MHz, DMSO- d 6 ) ⁇ 11.04 (s, 1H), 8.93 (s, 1H), 8.16 (s, 2H), 7.24 - 7.10 (m, 3H), 6.83 (dt, J 7.9, 3.5 Hz, 1H).
  • Example 18 was made analogously to Example 15 using methyl 2-amino-4-fluoro-1H-benzo[d]imidazole-7-carboxylate in place of 2-amino-4,5-difluoro-1 H -benzo[ d ]imidazole-7-carboxylate.
  • Example 19 was made analogously to Example 14 using methyl 2-amino-4-fluoro-1H-benzo[d]imidazole-7-carboxylate in place of 2-amino-4,5-difluoro-1 H- benzo[ d ]imidazole-7-carboxylate.
  • Example 20 was made analogously to Example 16 using methyl 2-amino-4-fluoro-1H-benzo[d]imidazole-7-carboxylate in place of 2-amino-4,5-difluoro-1 H- benzo[ d ]imidazole-7-carboxylate.
  • Example 21 was made analogously to Example 17 using methyl 2-amino-4-fluoro-1H-benzo[d]imidazole-7-carboxylate in place of 2-amino-4,5-difluoro-1 H- benzo[ d ]imidazole-7-carboxylate.
  • 1 H NMR (400 MHz, DMSO- d 6 ) ⁇ 10.95 (s, 1H), 8.93 (s, 1H), 8.32 (s, 2H), 7.24 - 7.05 (m, 4H), 6.83 (dd, J 8.5, 4.2 Hz, 1H).
  • Example 22 was made analogously to Example 13 (using methyl 2-amino-4-fluoro-1H-benzo[d]imidazole-7-carboxylate in place of 2-amino-4,5-difluoro-1 H- benzo[ d ]imidazole-7-carboxylate.
  • Methyl 4,5-difluoro-2-((2-morpholinoethyl)amino)-1H-benzo[d]imidazole-7-carboxylate Dissolved methyl 2,3-diamino-4,5-difluorobenzoate (50 mg, 0.25 mmol) in THF (3 ml), to the solution was added 4-(2-isothiocyanatoethyl)morpholine (0.43 g, 0.002 mmol) and triethylamine (0.36 g, 0.003 mol).
  • reaction mixture was heated at 80°C overnight, then to the reaction mixture was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.47 g, 0.002 mol), heated at 80°C for 1h.
  • the reaction mixture was diluted with EtOAc, and washed with NaHCO 3 saturated solution, organic layer was evaporated and the residue was purified with Combi-Flash column chromatography to afford 84mg desired product.
  • Example 23 was made analogously to Example 107 using the general procedure for hydroxy amidine formation. C 20 H 20 ClF 3 N 6 O 2 . 469.1 (M+1).
  • Example 24 was prepared analogously to Example 45, using 3-(2-(bromomethyl)-4,5-difluoro-1 H- benzo[ d ]midazol-7-yl)-4-(3-chlorophenyl)-1,2,4-oxadiazol-5(4 H )-one in place of 3-(2-(bromomethyl)-4,5-difluoro-1 H -benzo[ d ]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4 H )-one.
  • Example 25 was prepared analogously to Example 45 , using 3-(2-(bromomethyl)-4,5-difluoro-1 H -benzo[ d ]imidazol-7-yl)-4-(3-chlorophenyl)-1,2,4-oxadiazol-5(4 H )-one and cyclopropylmethanamine in place of 3-(2-(bromomethyl)-4,5-difluoro-1 H -benzo[ d ]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4 H )-one and 3-methoxypropylamine, respectively.
  • Example 26 was prepared analogously to Example 45, using 3-(2-(bromomethyl)-4,5-difluoro-1 H -benzo[ d ]imidazol-7-yl)-4-(3-chlorophenyl)-1,2,4-oxadiazol-5(4 H )-one and dimethylamine in place of 3-(2-(bromomethyl)-4,5-difluoro-1 H -benzo[ d ]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4 H )-one and 3-methoxypropylamine, respectively.
  • Example 27 was prepared analogously to Example 45, using 3-(2-(bromomethyl)-4,5-difluoro-1 H -benzo[ d ]imidazol-7-yl)-4-(3-chlorophenyl)-1,2,4-oxadiazol-5(4 H )-one and isopropylamine in place of 3-(2-(bromomethyl)-4,5-difluoro-1 H -benzo[ d ]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4 H )-one and 3-methoxypropylamine, respectively.
  • Example 28 was prepared analogously to Example 45, using 3-(2-(bromomethyl)-4,5-difluoro-1 H -benzo[ d ]imidazol-7-yl)-4-(3-chlorophenyl)-1,2,4-oxadiazol-5(4 H )-one and ethylamine in place of 3-(2-(bromomethyl)-4,5-difluoro-1 H- benzo[ d ]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4 H )-one and 3-methoxypropylamine, respectively.
  • Example 29 was prepared analogously to Example 46, using 4-(3-chlorophenyl)-3-(4,5-difluoro-2-(hydroxymethyl)-1 H -benzo[ d ]imidazol-7-yl)-1,2,4-oxadiazol-5(4 H )-one in place of 4-(3-chloro-4-fluorophenyl)-3-(4,5-difluoro-2-(hydroxymethyl)-1 H -benzo[ d ]imidazol-7-yl)-1,2,4-oxadiazol-5(4 H )-one.
  • Example 30 was prepared analogously to Example 45, using 3-(2-(bromomethyl)-4,5-difluoro-1 H -benzo[ d ]imidazol-7-yl)-4-(3-chlorophenyl)-1,2,4-oxadiazol-5(4 H )-one and methylamine in place of 3-(2-(bromomethyl)-4,5-difluoro-1 H- benzo[ d ]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4 H )-one and 3-methoxypropylamine, respectively.
  • Example 31 was prepared analogously to Example 45, using 3-(2-(bromomethyl)-4,5-difluoro-1 H -benzo[ d ]imidazol-7-yl)-4-(3-chlorophenyl)-1,2,4-oxadiazol-5(4 H )-one and ammonia (0.5 M solution in dioxane) in place of 3-(2-(bromomethyl)-4,5-difluoro-1 H -benzo[ d ]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4 H )-one and 3-methoxypropylamine, respectively.
  • N-(3-Chloro-4-fluorophenyl)-4,5-difluoro-2-morpholino-1H-benzo[d]imidazole-7-carboxamide was made analogously to Example 13 using methyl 4,5-difluoro-2-morpholino-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-7-carboxylate and 3-chloro-4-fluoroaniline in place of methyl 2-amino-4,5-difluoro-1 H- benzo[ d ]imidazole-7-carboxylate.
  • Example 32 was made analogously to Example 59 using N-(3-chloro-4-fluorophenyl)-4,5-difluoro-2-morpholino-1H-benzo[d]imidazole-7-carboxamide in place of N -(3-chloro-4-fluorophenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide.
  • Example 33 was made analogously to Example 22 using methyl 4-fluoro-2-((2-(methylsulfoyl)ethyl)amino)-1H-benzo[d]imidazole-7-carboxylate in place of methyl 2-amino-4-fluoro-1H-benzo[d]imidazole-7-carboxylate.
  • Example 34 was made analogously to Example 33 using 4-(2-isothiocyanatoethyl)morpholine in place of 1-isothiocyanato-2-(methylsulfonyl)ethane.
  • Example 35 was made analogously to Example 39 using 2-(methylsulfonyl)ethanamine in place of N 1 ,N 1 -dimethylpropane-1,3-diamine with an addition of triethylamine (1.2 eq) in the cyclization reaction.
  • Example 36 N -(3-Chloro-4-fluorophenyl)-2-((2-(4,4-difluoropiperidin-1-yl)ethyl)amino)-4,5-difluoro- N '-hydroxy-1 H -benzo[d]imidazole-7-carboximidamide
  • Example 36 was made analogously to Example 39 using 2-(4,4-difluoropiperidin-1-yl)ethanamine in place of N 1 ,N 1 -dimethylpropane-1,3-diamine.
  • Example 37 was made analogously to Example 39 using 1-morpholinopropan-2-amine in place of N1,N 1 -dimethylpropane-1,3-diamine.
  • N-(3-Chloro-4-fluorophenyl)-4,5-difluoro-2-(methylamino)-1H-benzo[d]imidazole-7-carboxamide was made analogously to Example 13 using methyl 4,5-difluoro-2-(methylamino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-7-carboxylate and 3-chloro-4-fluoroaniline in place of methyl 2-amino-4,5-difluoro-1 H -benzo[ d ]imidazole-7-carboxylate and stirring overnight at room temperature.
  • Example 38 was made analogously to Example 59 using N-(3-chloro-4-fluorophenyl)-4,5-difluoro-2-(methylamino)-1H-benzo[d]imidazole-7-carboxamide in place of N -(3-chloro-4-fluorophenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide.
  • the TFA salt of N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-(methylamino)-1H-benzo[d]imidazole-7-carboximidamide was isolated as a white solid. C 15 H 11 ClF 3 N 5 O. 370.05/371.98 (M+1).
  • Example 39 was made analogously to Example 59 using N-(3-chloro-4-fluorophenyl)-2-((3-(dimethylamino)propyl)amino)-4,5-difluoro-1H-benzo[d]imidazole-7-carboxamide in place of N -(3-chloro-4-fluorophenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide.
  • Methyl 4,5-difluoro-2-((2-methoxyethyl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1 H -benzo[ d ]imidazole-7-carboxylate was made analogously to Example 39 using 2-methoxyethanamine and triethylamine (1 equiv) in place of N , N -dimethylpropane-1,3-diamine.
  • N-(3-chloro-4-fluorophenyl)-4,5-difluoro-2-((2-methoxyethyl)amino)-1H-benzo[d]imidazole-7-carboxamide was made analogously to Example 39 using methyl 4,5-difluoro-2-((2-methoxyethyl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1 H- benzo[ d ]imidazole-7-carboxylate in place of methyl 2-((3-(dimethylamino)propyl)amino)-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1 H- benzo[ d ]imidazole-7-carboxylate.
  • Example 40 was made analogously to Example 59 using N-(3-chloro-4-fluorophenyl)-4,5-difluoro-2-((2-methoxyethyl)amino)-1H-benzo[d]imidazole-7-carboxamide in place of N -(3-chloro-4-fluorophenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide .
  • the TFA salt of N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((2-methoxyethyl)amino)-1H-benzo[d]imidazole-7-carboximidamide was isolated as a white solid.
  • Methyl 4,5-difluoro-2-((2-(pyrrolidin-1-yl)ethyl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1 H -benzo[ d ]imidazole-7-carboxylate was made analogously to Example 39 using 2-(pyrrolidin-1-yl)ethanamine in place of N,N- dimethylpropane-1,3-diamine.
  • N-(3-Chloro-4-fluorophenyl)-4,5-difluoro-2-((2-(pyrrolidin-1-yl)ethyl)amino)-1H-benzo[d]imidazole-7-carboxamide was made analogously to Example 39 using methyl 4,5-difluoro-2-((2-(pyrrolidin-1-yl)ethyl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1 H -benzo[ d ]imidazole-7-carboxylate in place of methyl 2-((3-(dimethylamino)propyl)amino)-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1 H -benzo[ d ]imidazole-7-carboxylate.
  • Example 41 was made analogously to Example 59 using N-(3-chloro-4-fluorophenyl)-4,5-difluoro-2-((2-(pyrrolidin-1-yl)ethyl)amino)-1H-benzo[d]imidazole-7-carboxamide in place of N -(3-chloro-4-fluorophenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide.
  • Methyl 2-((2-(diethylamino)ethyl)amino)-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1 H -benzo[ d ]imidazole-7-carboxylate was made analogously to Example 39 using N , N -diethylethane-1,2-diamine in place of N,N- dimethylpropane-1,3-diamine.
  • N-(3-chloro-4-fluorophenyl)-2-((2-(diethylamino)ethyl)amino)-4,5-difluoro-1H-benzo[d]imidazole-7-carboxamide was made analogously to Example 39 using methyl 2-((2-(diethylamino)ethyl)amino)-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1 H -benzo[ d ]imidazole-7-carboxylate in place of methyl 2-((3-(dimethylamino)propyl)amino)-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1 H -benzo[ d ]imidazole-7-carboxylate.
  • Example 42 was made analogously to Example 59 using N-(3-chloro-4-fluorophenyl)-2-((2-(diethylamino)ethyl)amino)-4,5-difluoro-1H-benzo[d]imidazole-7-carboxamide in place of N -(3-chloro-4-fluorophenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide .
  • Methyl 2-((2-(dimethylamino)ethyl)amino)-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1 H -benzo[ d ]imidazole-7-carboxylate was made analogously to Example 39 using N , N -dimethylethane-1,2-diamine in place of N,N- dimethylpropane-1,3-diamine.
  • N-(3-Chloro-4-fluorophenyl)-2-((2-(dimethylamino)ethyl)amino)-4,5-difluoro-1H-benzo[d]imidazole-7-carboxamide was made analogously to Example 39 using methyl 2-((2-(dimethylamino)ethyl)amino)-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1 H -benzo[ d ]imidazole-7-carboxylate in place of methyl 2-((3-(dimethylamino)propyl)amino)-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1 H -benzo[ d ]imidazole-7-carboxylate.
  • Example 43 was made analogously to Example 59 using N-(3-chloro-4-fluorophenyl)-2-((2-(dimethylamino)ethyl)amino)-4,5-difluoro-1H-benzo[d]imidazole-7-carboxamide in place of N -(3-chloro-4-fluorophenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide .
  • Example 44 was made analogously to Example 53 using 1-methylpiperidine-3-carboxylic acid in place of 3-(dimethylamino)propanoic acid.
  • the TFA salt of 4,5-difluoro-2-(1-methylpiperidin-3-yl)-1H-benzo[d]imidazole-7-carboxylic acid was isolated as a colorless oil.
  • Example 44 was made analogously to Example 59 using N-(3-chloro-4-fluorophenyl)-4,5-difluoro-2-(1-methylpiperidin-3-yl)-1H-benzo[d]imidazole-7-carboxamide in place of N -(3-chloro-4-fluorophenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide .
  • the TFA salt of N-(3-chlorophenyl)-4,5-difluoro-N'-hydroxy-2-(1-methylpiperidin-3-yl)-1H-benzo[d]imidazole-7-carboximidamide was isolated as a white solid.
  • Methyl 4,5-difluoro-2-(methoxymethyl)-1H-benzo[d]imidazole-7-carboxylate A mixture of methyl 2,3-diamino-4,5-difluorobenzoate (2.0 g, 9.9 mmol) in methoxyacetic acid (23 mL) was stirred at 120 °C for 3 hr. To the mixture was added saturated sodium bicarbonate and the aqueous layer was washed three times with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, absorbed onto silica and purified by silica gel chromatography to give the desired product. C 11 H 10 F 2 N 2 O 3 . 257.3 (M+1).
  • Example 47 was made analogously to Example 45 using 0.5 M ammonia in dioxane in place of 3-methoxypropylamine. C 15 H 11 ClF 3 N 5 O. 370.1 (M+1).
  • Example 48 was made analogously to Example 45 using 2 M methylamine in tetrahydrofuran in place of 3-methoxypropylamine.
  • Example 49 was made analogously to Example 45 using cyclopropylmethylamine in place of 3-methoxypropylamine. C 19 H 17 ClF 3 N 5 O.424.0 (M+1).
  • Example 50 was made analogously to Example 45 using 2 M ethylamine in tetrahydrofuran in place of 3-methoxypropylamine. C 17 H 15 ClF 3 N 5 O. 398.0 (M+1).
  • Example 51 was made analogously to Example using isopropylamine in place of 3-methoxypropylamine. C 18 H 17 ClF 3 N 5 O. 412.1 (M+1).
  • Example 52 was made analogously to Example 45 using dimethylamine in place of 3-methoxypropylamine. C 17 H 15 ClF 3 N 5 O. 398.1 (M+1).
  • Example 53 was made analogously to Example 95 C 18 H 17 ClF 3 N 5 O. 411.11 (M+1).
  • N-(3-bromo-4-fluorophenyl)-2-(2-(dimethylamino)ethyl)-6,7-difluoro-1H-benzo[d]imidazole-4-carboxamide was made analogously to Example 53 using 3-bromo-4-fluoroaniline in place of 3-chloro-4-fluoroaniline.
  • Example 54 was made analogously to Example 95. C 18 H 17 BrF 3 N 5 O. 456.1 (M+1).
  • N-(3-bromophenyl)-2-(2-(dimethylamino)ethyl)-6,7-difluoro-1H-benzo[d]imidazole-4-carboxamide was made analogously to Example 53 using 3-bromoaniline in place of 3-chloro-4-fluoroaniline.
  • Example 55 was made analogously to Example 95. C 18 H 18 BrF 2 N 5 O. 438.10.
  • N-(3-chlorophenyl)-2-(2-(dimethylamino)ethyl)-6,7-difluoro-1H-benzo[d]imidazole-4-carboxamide was made analogously to Example 53 using 3-chloroaniline in place of 3-chloro-4-fluoroaniline.
  • Example 56 was made analogously to Example 95 C 18 H 18 ClF 2 N 5 O. 394.12 (M+1).
  • N-(3-chloro-4-fluorophenyl)-4,5-difluoro-2-(2-hydroxyethyl)-1H-benzo[d]imidazole-7-carboxamide was made analogously to Example 183 using Ethyl 2-(7-((3-chloro-4-fluorophenyl)carbamoyl)-4,5-difluoro-1H-benzo[d]imidazol-2-yl)acetate.
  • N-(3-chloro-4-fluorophenyl)-4,5-difluoro-2-(2-((triisopropylsilyl)oxy)ethyl)-1H-benzo[d]imidazole-7-carboxamide was made analogously to Example 183 using N-(3-chloro-4-fluorophenyl)-4,5-difluoro-2-(2-hydroxyethyl)-1H-benzo[d]imidazole-7-carboxamide.
  • N-(3-chloro-4-fluorophenyl)-4,5-difluoro-2-(2-((triisopropylsilyl)oxy)ethyl)-1H-benzo[d]imidazole-7-carbothioamide was made analogously to Example 183 using N-(3-chloro-4-fluorophenyl)-4,5-difluoro-2-(2-((triisopropylsilyl)oxy)ethyl)-1H-benzo[d]imidazole-7-carboxamide.
  • Example 57 was made analogously to Example 112 using 2-(7-(4-(3-chloro-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-4,5-difluoro-1-(methylsulfonyl)-1H-benzo[d]imidazol-2-yl)ethyl methanesulfonate in place of 2-(7-(4-(3-chloro-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-3-(methylsulfonyl)-3H-imidazo[4,5-b]pyridin-2-yl)ethyl methanesulfonate.
  • Example 58 was made analogously to Example 57 using 2-(7-(4-(3-chloro-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-4,5-difluoro-1-(methylsulfonyl)-1H-benzo[d]imidazol-2-yl)ethyl methanesulfonate and diethylamine in place of 2-(7-(4-(3-chloro-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-3-(methylsulfonyl)-3H-imidazo[4,5-b]pyridin-2-yl)ethyl methanesulfonate and methylamine.
  • N-(3-chloro-4-fluorophenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide 122 mg, 0.42 mmol
  • PCl 5 (0.63 mmol
  • the reaction was cooled to rt and concentrated in vacuo.
  • the residue was dissolved in a pre-mixed solution of hydroxylamine (50% aqueous solution, 4.0 mmol) and ethanol (2 mL) and the reaction was allowed to stir at rt for 10 minutes.
  • Example 60 was made analogously to Example 59 using 5-chloro-2-fluoroaniline in place of 3-chloro-4-fluoroaniline.
  • Example 61 was made analogously to Example 59 using 5-bromo-2,4-difluoroaniline in place of 3-chloro-4-fluoroaniline.
  • 1 H NMR (400 MHz, DMSO- d 6 ) ⁇ 11.03 (s, 1H), 8.71 (s, 1H), 8.59 (s, 1H), 8.36 (d, J 4.8 Hz, 1H), 7.34 - 7.21 (m, 3H).
  • Example 62 was made analogously to Example 59 using 5-chloro-2,4-difluoroaniline in place of 3-chloro-4-fluoroaniline.
  • Example 63 was made analogously to Example 59 using 3,5-dichloro-4-fluoroaniline in place of 3-chloro-4-fluoroaniline.
  • Example 64 was made analogously to Example 59 using 3-chloro-2,4-difluoroaniline in place of 3-chloro-4-fluoroaniline.
  • Example 65 was made analogously to Example 59 using 3-cyclopropyl-4-fluoroaniline in place of 3-chloro-4-fluoroaniline. C 16 H 14 FN 5 O. 312.1 (M+1).
  • Example 66 was made analogously to Example 59 using 4-(trifluoromethoxy)aniline in place of 3-chloro-4-fluoroaniline. C 14 H 10 F 3 N 5 O 2 . 338.1 (M+1).
  • Example 69 was made analogously to Example 59 using benzofuran-7-amine in place of 3-chloro-4-fluoroaniline. C 15 H 11 N 5 O 2 . 294.1 (M+1).
  • Example 70 was made analogously to Example 59 using benzofuran-5-amine in place of 3-chloro-4-fluoroaniline. C 15 H 11 N 5 O 2 . 294.1 (M+1).
  • Example 71 was made analogously to Example 59 using acid and 5-bromo-2-fluoroaniline in place of 3-chloro-4-fluoroaniline.
  • 1 H NMR (400 MHz, DMSO- d 6 ) ⁇ 11.16 (s, 1H), 10.06 (s, 1H), 8.74 (s, 1H), 8.57 (s, 1H), 8.35 (d, J 5.1 H, 1H), 7.25 (s, 1H), 7.14 - 6.92 (m, 3H).
  • Example 72 was made analogously to Example 59 using 5-bromo-3-fluoroaniline in place of 3-chloro-4-fluoroaniline. C 13 H 9 BrFN 5 O. 350.1/352.1 (M+1).
  • Example 73 was made analogously to Example 59 using 3-(trifluoromethyl)aniline in place of 3-chloro-4-fluoroaniline.
  • Example 74 was made analogously to Example 59 using 2,2-difluorobenzo[d][1,3]dioxol-5-amine in place of 3-chloro-4-fluoroaniline.
  • Example 75 was made analogously to Example 59 using 3-fluoro-5-(trifluoromethyl)aniline in place of 3-chloro-4-fluoroaniline. C 14 H 9 F 4 N 5 O. 340.1 (M+1).
  • N-(2,5-dichlorophenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide (40 mg, 0.13 mmol) was dissolved in POCl 3 (2 mL) and PCl 5 (0.195 mmol) was added. The reaction was heated to 80 °C overnight, allowed to cool to rt, and concentrated in vacuo. The crude was dissolved in a pre-mixed solution of hydroxylamine (50% in water, 1.0 mmol) and ethanol (2 mL) and allowed to stir at rt for 10 mins then concentrated in vacuo.
  • N-(3-bromo-4-fluorophenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide 150 mg, 0.448 mmol
  • phenyl boronic acid 2.0 mmol
  • degassed THF 2.0 mL
  • water 0.50 mL
  • PdCl 2 (dppf) 0.090 mmol
  • K 2 CO 3 2.0 mmol
  • N-(6-fluoro-[1,1'-biphenyl]-3-yl)-1H-imidazo[4,5-b]pyridine-7-carboxamide (100 mg, 0.301 mmol) was dissolved in POCl 3 , PCl 5 (2.0 mmol) was added, and the reaction was heated to 80 °C overnight. The reaction was allowed to cool to rt and concentrated in vacuo. The crude was dissolved in a pre-mixed solution of hydroxylamine (50% in water, 3.0 mmol) and ethanol (2 mL) and allowed to stir at rt for 10 mins.
  • N-(3-bromo-4-fluorophenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide 100 mg, 0.298 mmol
  • PdCl 2 (PPh 3 ) 2 0.015 mmol
  • CuI 0.0298 mmol
  • N-(3-(but-1-yn-1-yl)-4-fluorophenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide (56 mg, 0.182 mmol) was dissolved in POCl 3 (2 mL) and PCl 5 (0.272 mmol) was added and the reaction was heated to 80 °C for 45 mins. The reaction was allowed to cool to rt and concentrated in vacuo. The material was dissolved in a pre-mixed solution of hydroxylamine (50% in water, 2.0 mmol) and ethanol (2 mL) and allowed to stir at rt for 10 mins.
  • Example 79 was made analogously to Example 78 using ethynylcyclopropane (5 eq) in place of but-1-yne. C 18 H 14 FN 5 O. 336.1 (M+1).
  • N -(3-bromophenyl)- N' -hydroxy-1 H -imidazo[4,5- b ]pyridine-7-carboximidamide N -(3-bromophenyl)- N' -hydroxy-1 H -imidazo[4,5- b ]pyridine-7-carboximidamide.
  • N -(3-bromophenyl)-1 H -imidazo[4,5- b ]pyridine-7-carboxamide 0.062 g, 0.195 mmol
  • phosphoryl chloride 0.18 mL, 1.95 mmol
  • DCE 2 mL
  • phosphorus pentachloride 0.061 g, 0.293 mmol
  • Example 81 was synthesized analogously to Example 80, using N-(3-bromo-4-fluorophenyl)-1 H -imidazo[4,5- b ]pyridine-7-carboxamide in place of N -(3-bromophenyl)-1 H -imidazo[4,5- b ]pyridine-7-carboxamide. (C 13 H 9 BrFN 5 O. 350.0/352.0 [M+1] + .
  • N -(3-chlorophenyl)-1 H -imidazo[4,5- b ]pyridine-7-carboxamide was synthesized analogously to Example 80 using 3-chloroaniline in place of 3-bromoaniline.
  • Example 82 was synthesized analogously to Example 80, using N-(3-chlorophenyl)-1 H -imidazo[4,5- b ]pyridine-7-carboxamide in place of N -(3-bromophenyl)-1 H -imidazo[4,5- b ]pyridine-7-carboxamide.
  • N -(4-fluoro-3-(trifluoromethyl)phenyl)-1 H -imidazo[4,5- b ]pyridine-7-carboxamide was synthesized analogously to Example 80 using 4-fluoro-3-(trifluoromethyl)aniline in place of 3-bromoaniline.
  • Example 83 was synthesized analogously to Example 80, using N- (4-fluoro-3-(trifluoromethyl)phenyl)-1 H -imidazo[4,5- b ]pyridine-7-carboxamide in place of N -(3-bromophenyl)-1 H -imidazo[4,5- b ]pyridine-7-carboxamide.
  • Example 84 was synthesized analogously to Example 80, using N -(4-fluoro-3-(prop-1-yn-1-yl)phenyl)-1 H -imidazo[4,5- b ]pyridine-7-carboxamide in place of N -(3-bromophenyl)-1 H -imidazo[4,5- b ]pyridine-7-carboxamide.
  • N -(3-bromo-4-chlorophenyl)-1 H -imidazo[4,5- b ]pyridine-7-carboxamide was synthesized analogously to Example 80, using 3-bromo-4-chloroaniline in place of 4-fluoro-3-(prop-1-yn-1-yl)aniline.
  • Example 85 was synthesized analogously to Example 80 using N-(3-bromo-4-chlorophenyl)-1 H -imidazo[4,5- b ]pyridine-7-carboxamide in place of N- (3-bromophenyl)-1 H -imidazo[4,5- b ]pyridine-7-carboxamide.
  • Example 86 was synthesized analogously to Example 80, using 3,4-dichloroaniline in place of 3-bromoaniline. C 13 H 8 Cl 2 N 4 O. 307.0 [M+1] + .
  • Example 86 was synthesized analogously to Example 80, using N- (3,4-dichlorophenyl)-1 H -imidazo[4,5- b ]pyridine-7-carboxamide in place of N -(3-bromophenyl)-1 H -imidazo[4,5- b ]pyridine-7-carboxamide.
  • Example 87 was synthesized analogously to Example 80, using N -(4-chlorophenyl)-1 H -imidazo[4,5- b ]pyridine-7-carboxamide in place of N -(3-bromophenyl)-1 H -imidazo[4,5- b ]pyridine-7-carboxamide.
  • N -(4-bromophenyl)-1 H -imidazo[4,5- b ]pyridine-7-carboxamide was synthesized analogously to Example 80, using 4-bromoaniline in place of 3-bromoaniline.
  • Example 88 was synthesized analogously to Example 80, using N -(4-bromophenyl)-1 H -imidazo[4,5- b ]pyridine-7-carboxamide in place of N -(3-bromophenyl)-1 H -imidazo[4,5- b ]pyridine-7-carboxamide.
  • N -(4-fluorophenyl)-1 H -imidazo[4,5- b ]pyridine-7-carboxamide was synthesized analogously to Example 80 using 5-fluoroaniline in place of 3-bromoaniline. C 13 H 9 FN 4 O. 257.0 [M+1] + .
  • Example 89 was synthesized analogously to Example 80, using N -(4-fluorophenyl)-1 H -imidazo[4,5- b ]pyridine-7-carboxamide in place of N -(3-bromophenyl)-1 H -imidazo[4,5- b ]pyridine-7-carboxamide.
  • N -(3-cyano-4-fluorophenyl)-1 H -imidazo[4,5-b]pyridine-7-carboxamide was synthesized analogously to Example 80, using 3-cyano-4-fluoroaniline in place of 3-bromoaniline.
  • Example 90 was synthesized analogously to Example 80, using N -(3-cyano-4-fluorophenyl)-1 H -imidazo[4,5- b ]pyridine-7-carboxamide in place of N -(3-bromophenyl)-1 H -imidazo[4,5- b ]pyridine-7-carboxamide.
  • N -(4-(trifluoromethyl)phenyl)-1 H -imidazo[4,5- b ]pyridine-7-carboxamide was synthesized analogously to Example 84, using 4-(trifluoromethyl)aniline in place of 4-fluoro-3-(prop-1-yn-1-yl)aniline.
  • Example 91 was synthesized analogously to Example 80 using N -(4-(trifluoromethyl)phenyl)-1 H -imidazo[4,5- b ]pyridine-7-carboxamide in place of N -(3-bromophenyl)-1 H -imidazo[4,5- b ]pyridine-7-carboxamide.
  • N -(3-methoxyphenyl)-1 H -imidazo[4,5- b ]pyridine-7-carboxamide was synthesized analogously to Example 80, using 3-methoxyaniline in place of 3-bromoaniline.
  • Example 92 was synthesized analogously to Example 80, using N -(3-methoxyphenyl)-1 H -imidazo[4,5- b ]pyridine-7-carboxamide in place of N -(3-bromophenyl)-1 H -imidazo[4,5- b ]pyridine-7-carboxamide.
  • N -(4-fluoro-3-isopropylphenyl)-1 H -imidazo[4,5-b]pyridine-7-carboxamide was synthesized analogously to Example 80, using 4-fluoro-3-isopropylaniline in place of 3-bromoaniline.
  • Example 93 was synthesized analogously to Example 80, using N -(4-fluoro-3-isopropylphenyl)-1 H -imidazo[4,5- b ]pyridine-7-carboxamide in place of N -(3-bromophenyl)-1 H -imidazo[4,5- b ]pyridine-7-carboxamide.
  • N -( p -tolyl)-1 H -imidazo[4,5- b ]pyridine-7-carboxamide was synthesized analogously to Example 84, using p -toluidine in place of 4-fluoro-3-(prop-1-yn-1-yl)aniline. C 14 H 12 N 4 O. 253.1 [M+1] + .
  • Example 94 was synthesized analogously to Example 80, using N- ( p -tolyl)-1 H- imidazo[4,5- b ]pyridine-7-carboxamide in place of N -(3-bromophenyl)-1 H -imidazo[4,5- b ]pyridine-7-carboxamide.
  • N-(3-ethynylphenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide A mixture of N-(3-ethynylphenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide (41 mg, 0.155 mmol), phosphorous pentachloride (48 mg, 0.233 mmol) in phosphoryl chloride (0.3mL) and 1,2-dichloroethane (0.3 mL) were stirred at 80 °C for 2 hr. The reaction mixture was concentrated and suspended in ethanol (2 mL) and to this mixture was added 50% hydroxylamine in water (0.265 mL, 4.33 mmol).
  • N-(3-ethylphenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide was prepared as described in Example 95.
  • N-(3-ethynyl-4-fluorophenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide was made analogously to Example 95 using 3-ethynyl-4-fluoroaniline in place of 3-ethynylaniline.
  • Example 97 was made analogously to Example 95 C 15 H 10 FN 5 O. 295.09 (M+1).
  • N-(3-(difluoromethyl)phenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide was made analogously to Example 95 using 3-(difluoromethyl)aniline in place of 3-ethynylaniline. C14H10F2N4O. 289.10 (M+1).
  • Example 98 was made analogously to Example 95 using N-(3-(difluoromethyl)phenyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide.
  • N-(3-(trifluoromethoxy)phenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide was made analogously to Example 95 using 3-(trifluoromethoxy)aniline in place of 3-ethynylaniline.
  • Example 99 was made analogously to Example 95 using N-(3-(trifluoromethoxy)phenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide.
  • N-phenyl-1H-imidazo[4,5-b]pyridine-7-carboxamide was made analogously to Example 95 using aniline in place of 3-ethynylaniline. C13H10N4O. 239.10 (M+1).
  • Example 100 was made analogously to Example 95 using N-phenyl-1H-imidazo[4,5-b]pyridine-7-carboxamide. C 13 H 11 N 5 O.
  • N-(4-fluoro-3-(trifluoromethoxy)phenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide was made analogously to Example 95 using 4-fluoro-3-(trifluoromethoxy)aniline in place of 3-ethynylaniline.
  • Example 101 was made analogously to Example 95 using N-(4-fluoro-3-(trifluoromethoxy)phenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide.
  • N-(naphthalen-2-yl)-1H-imidazo[4,5-b]pyridine-7-carboxamide was made analogously to Example 95 using naphthalen-2-amine in place of 3-ethynylaniline. C 17 H 12 N 4 O. 289.10 (M+1).
  • N-Hydroxy-N-(naphthalen-2-yl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide (Example 102) and N-(3-chloronaphthalen-2-yl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide (Example 103) were made analogously to Example 95 using N-(naphthalen-2-yl)-1H-imidazo[4,5-b]pyridine-7-carboxamide give two products (N-hydroxy-N-(naphthalen-2-yl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide and N-(3-chloronaphthalen-2-yl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide).
  • N-(3-Chloronaphthalen-2-yl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide was prepared according to Example 102. C 17 H 12 ClN 5 O. 338.11(M+1).
  • N-(naphthalen-1-yl)-1H-imidazo[4,5-b]pyridine-7-carboxamide was made analogously to Example 95 using naphthalen-1-amine in place of 3-ethynylaniline. C 17 H 12 N 4 O. 289.10 (M+1).
  • N'-hydroxy-N-(naphthalen-1-yl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide (Example 104) and N-(4-chloronaphthalen-1-yl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide (Example 105) were made analogously to Example 95 using N-(naphthalen-1-yl)-1H-imidazo[4,5-b]pyridine-7-carboxamide give two products (N'-hydroxy-N-(naphthalen-1-yl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide and N-(4-chloronaphthalen-1-yl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide).
  • Example 105 was made analogously to Example 104. C 17 H 12 ClN 5 O. 338.11(M+1).
  • N-(4-fluoro-3-methoxyphenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide was made analogously to Example 95 using 4-fluoro-3-methoxyanilinein place of 3-ethynylaniline. C 14 H 11 FN 4 O 2 . 286.09 (M+1).
  • Example 106 was made analogously to Example 95 using 4-fluoro-3-methoxyphenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide. C 14 H 12 FN 5 O 2 . 302.10 (M+1).
  • N-(3-Chloro-4-fluorophenyl)-2-methyl-1H-imidazo[4,5-b]pyridine-7-carboxamide A mixture of 2,3-diamino-N-(3-chloro-4-fluorophenyl)isonicotinamide (1.06 g, 3.77 mmol) in acetic acid (11 mL) was stirred at 180 °C for 1 hr in a microwave. Water was added and the resulting precipitate was filtered and dried on high vac to give the desired product. C 14 H 10 ClFN 4 O. 305.1 (M+1).
  • N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-methyl-1H-imidazo[4,5-b]pyridine-7-carboximidamide A mixture of N-(3-Chloro-4-fluorophenyl)-2-methyl-1H-imidazo[4,5-b]pyridine-7-carboxamide (132 mg, 0.433 mmol), phosphorous pentachloride (135 mg, 0.650 mmol) in phosphoryl chloride (2 mL) and 1,2-dichloroethane (2 mL) were stirred at 80 °C for 2.5 hr.
  • N-(3-chloro-4-fluorophenyl)-2-ethyl-1H-imidazo[4,5-b]pyridine-7-carboxamide was made analogously to Example 107 using propionic acid in place of acetic acid.
  • Example 108 was made analogously to Example 107 using N-(3-chloro-4-fluorophenyl)-2-ethyl-1H-imidazo[4,5-b]pyridine-7-carboxamide in place of N-(3-Chloro-4-fluorophenyl)-2-methyl-1H-imidazo[4,5-b]pyridine-7-carboxamide.
  • N-(3-chloro-4-fluorophenyl)-2-cyclopropyl-1H-imidazo[4,5-b]pyridine-7-carboxamide was made analogously to Example 107 using cyclopropanecarboxylic acid in place of acetic acid.
  • Example 109 was made analogously to Example 107 using N-(3-chloro-4-fluorophenyl)-2-cyclopropyl-1H-imidazo[4,5-b]pyridine-7-carboxamide in place of N-(3-Chloro-4-fluorophenyl)-2-methyl-1H-imidazo[4,5-b]pyridine-7-carboxamide.
  • Example 110 N -(3-Chloro-4-fluorophenyl)- N' -hydroxy-2-(methoxymethyl)-1 H- imidazo[4,5-b]pyridine-7-carboximidamide
  • N-(3-chloro-4-fluorophenyl)-2-(methoxymethyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide was made analogously to Example 107 using methoxyacetic acid in place of acetic acid. C 15 H 12 ClFN 4 O 2 . 334.9 (M+1).
  • the reaction mixture was concentrated and suspended in ethanol (20 mL) and to this mixture was added 50% hydroxylamine in water (4.8 mL, 78 mmol). The reaction mixture stirred for 1 hr and was concentrated. Water and aqueous saturated sodium bicarbonate were added and the solid was filtered and dried on high vac. The solid was suspended in ethyl acetate (100 mL) and to this mixture was added carbonyldiimidazole (1.90 g, 11.7 mmol). The mixture was stirred for 18 hr and concentrated. The residue was purified by silica gel chromatography to give the desired product (871 mg). C 16 H 11 ClFN 5 O 3 . 376.3 (M+1).
  • Example 110 was made analogously to Example 95 using N-(3-chloro-4-fluorophenyl)-2-(methoxymethyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide.
  • Example 111 4-(3-Chloro-4-fluorophenyl)-3-(2-(hydroxymethyl)-1H-imidazo [4,5-b]pyridin-7-yl)-1,2,4-oxadiazol-5(4 H )-one
  • N-(3-chloro-4-fluorophenyl)-2-((dimethylamino)methyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide A solution of 4-(3-chloro-4-fluorophenyl)-3-(2-(chloromethyl)-1-(methylsulfonyl)-1H-imidazo[4,5-b]pyridin-7-yl)-1,2,4-oxadiazol-5(4H)-one (30 mg, 0.065 mmol) and dimethylamine (2 M in THF, 0.655 mL, 1.3 mmol) in acetonitrile (1 mL) was stirred at 65 °C for 3 hr min.
  • Example 114 was made analogously to Example 112 using 2 M ethylamine in THF in place of morpholine. C 16 H 16 ClFN 6 O. 363.1 (M+1).
  • Example 115 was made analogously to Example 112 using benzylamine in place of morpholine. C 21 H 18 ClFN 6 O. 425.1 (M+1).
  • Example 116 was made analogously to Example 112 using isopropylamine in place of morpholine. C 17 H 18 ClFN 6 O. 377.1 (M+1).
  • Example 117 was made analogously to Example 112 using cyclopropylmethylamine in place of morpholine. C 18 H 18 ClFN 6 O. 388.9 (M+1).
  • Example 118 was made analogously to Example 112 using 2,2,2-trifluoroethylamine in place of morpholine. C 16 H 13 ClF 4 N 6 O. 416.7 (M+1).
  • Example 119 was made analogously to Example 112 using cyclopropylamine in place of morpholine. C 17 H 16 ClFN 6 O. 374.9 (M+1).
  • Example 120 N -(3-Chloro-4-fluorophenyl)- N' -hydroxy-2-(((3-methoxypropyl)amino)methyl)-1 H- imidazo[4,5-b]pyridine-7-carboximidamide
  • Example 120 was made analogously to Example 112 using 3-methoxypropylamine in place of morpholine. C 18 H 20 ClFN 6 O 2 . 407.1 (M+1).
  • Example 121 was made analogously to Example 112 using pyridin-2-ylmethanamine in place of morpholine. C 20 H 17 ClFN 7 O. 426.1 (M+1).
  • Example 122 N -(3-Chloro-4-fluorophenyl)- N' -hydroxy-2-(((3-methoxypropyl)(methyl)amino)methyl)-1 H -imidazo[4,5-b]pyridine-7-carboximidamide
  • Example 122 was made analogously to Example 112 using 3-(2-(bromomethyl)-1H-imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one and 3-methoxy-N-methylpropan-1-amine in place of (7-(4-(3-chloro-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-1-(methylsulfonyl)-1H-imidazo[4,5-b]pyridin-2-yl)methyl methanesulfonate and morpholine.
  • Example 123 was made analogously to Example 112 using 4-(3-chloro-4-fluorophenyl)-3-(2-(chloromethyl)-1-(methylsulfonyl)-1H-imidazo[4,5-b]pyridin-7-yl)-1,2,4-oxadiazol-5(4H)-one and 2-methoxybenzylamine in place of (7-(4-(3-chloro-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-1-(methylsulfonyl)-1H-imidazo[4,5-b]pyridin-2-yl)methyl methanesulfonate and morpholine.
  • Example 124 was made analogously to Example 112 using 2-methoxyethylamine in place of morpholine.C 17 H 18 ClFN 6 O 2 . 393.1(M+1).
  • Example 125 was made analogously to Example 112 using 2-(pyridin-2-yl)ethanamine in place of morpholine. C 21 H 19 ClFN 7 O. 440.1 (M+1).
  • Example 126 was made analogously to Example 112 using 3-picolylamine in place of morpholine. C 20 H 17 ClFN 7 O. 426.1 (M+1).
  • Example 127 was made analogously to Example 112 using 4-(3-chloro-4-fluorophenyl)-3-(2-(chloromethyl)-1-(methylsulfonyl)-1H-imidazo[4,5-b]pyridin-7-yl)-1,2,4-oxadiazol-5(4H)-one and (tetrahydro-2H-pyran-2-yl)methanamine in place of (7-(4-(3-chloro-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-1-(methylsulfonyl)-1H-imidazo[4,5-b]pyridin-2-yl)methyl methanesulfonate and morpholine.
  • Example 129 N -(3-Chloro-4-fluorophenyl)- N' -hydroxy-2-((((tetrahydro-2 H -pyran-3-yl)methyl)amino)methyl)-1 H -imidazo[4,5-b]pyridine-7-carboximidamide
  • Example 129 was made analogously to Example 112 using (tetrahydro-2H-pyran-3-yl)methanamine in place of morpholine. C 20 H 22 ClFN 6 O 2 . 433.1 (M+1).
  • Example 130 was made analogously to Example 112 using pyrimidin-2-ylmethanamine in place of morpholine. C 19 H 16 ClFN 8 O. 427.1 (M+1).
  • Example 131 was made analogously to Example 112 using 3-morpholinopropan-1-amine in place of morpholine. C 21 H 25 ClFN 7 O 2 . 462.2 (M+1).
  • Example 132 was made analogously to Example 112 using 4-(3-chloro-4-fluorophenyl)-3-(2-(chloromethyl)-1-(methylsulfonyl)-1H-imidazo[4,5-b]pyridin-7-yl)-1,2,4-oxadiazol-5(4H)-one and tetrahydro-2H-pyran-4-amine in place of (7-(4-(3-chloro-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-1-(methylsulfonyl)-1H-imidazo[4,5-b]pyridin-2-yl)methyl methanesulfonate and morpholine.
  • Example 133 was made analogously to Example 112 using 4-picolylamine in place of morpholine. C 20 H 17 ClFN 7 O. 426.1 (M+1).
  • Example 134 was made analogously to Example 112 using pyrazin-2-ylmethanamine in place of morpholine. C 19 H 16 ClFN 8 O. 427.1 (M+1).
  • Example 135 N -(3-Chloro-4-fluorophenyl)- N' -hydroxy-2-((((tetrahydrofuran-3-yl)methyl)amino)methyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Example 135 was made analogously to Example 112 using 4-(3-chloro-4-fluorophenyl)-3-(2-(chloromethyl)-1-(methylsulfonyl)-1H-imidazo[4,5-b]pyridin-7-yl)-1,2,4-oxadiazol-5(4H)-one and (tetrahydrofuran-3-yl)methanamine in place of (7-(4-(3-chloro-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-1-(methylsulfonyl)-1H-imidazo[4,5-b]pyridin-2-yl)methyl methanesulfonate and morpholine.
  • Example 136 was made analogously to Example 112 using N,N-dimethylethane-l,2-diamine in place of morpholine. C 18 H 21 ClFN 7 O. 406.1 (M+1).
  • Example 137 was made analogously to Example 112 using 2-(pyrimidin-2-yl)ethanamine in place of morpholine. C 20 H 18 ClFN 8 O. 441.1 (M+1).
  • Example 138 N -(3-Chloro-4-fluorophenyl)- N' -hydroxy-2-(((3-hydroxypropyl)amino)methyl)-1 H -imidazo[4,5-b]pyridine-7-carboximidamide
  • Example 138 was made analogously to Example 112 using 3-aminopropanol in place of morpholine. C 17 H 18 ClFN 6 O 2 . 393.1 (M+1).
  • Example 139 was synthesized analogously to Example 112 using pyrrolidine in place of morpholine. C 18 H 18 ClFN 6 O. 389.1 [M+1] + .
  • Example 140 N -(3-Chloro-4-fluorophenyl)- N '-hydroxy-2-(piperidin-1-ylmethyl)-1 H -imidazo[4,5- b ]pyridine-7-carboximidamide
  • Example 140 was synthesized analogously to Example 112 using piperidine in place of morpholine. C 19 H 20 ClFN 6 O. 403.1 [M+1] + .
  • Example 141 was synthesized analogously to Example 112 using 3-(2-(bromomethyl)-1 H -imidazo[4,5- b ]pyridin-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4 H )-one and 2,2-dimethylpropan-1-amine in place of (7-(4-(3-chloro-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-1-(methylsulfonyl)-1 H- imidazo[4,5- b ]pyridin-2-yl)methyl methanesulfonate and morpholine, respectively.
  • Example 142 N -(3-Chloro-4-fluorophenyl)-2-(((2,2-difluoroethyl)amino)methyl)- N' -hydroxy-1 H -imidazo[4,5- b ]pyridine-7-carboximidamide
  • Example 142 was synthesized analogously to Example 112 using 3-(2-(bromomethyl)-1 H -imidazo[4,5- b ]pyridin-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4 H )-one and 2,2-difluoroethylamine in place of (7-(4-(3-chloro-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-1-(methylsulfonyl)-1 H- imidazo[4,5- b ]pyridin-2-yl)methyl methanesulfonate and morpholine, respectively.
  • Example 143 was synthesized analogously to Example 112 using 3-(2-(bromomethyl)-1 H -imidazo[4,5- b ]pyridin-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4 H )-one and 3-amino-2,2-dimethylpropan-1-ol in place of (7-(4-(3-chloro-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-1-(methylsulfonyl)-1 H- imidazo[4,5- b ]pyridin-2-yl)methyl methanesulfonate and morpholine, respectively.
  • Example 144 was synthesized analogously to Example 112 using 3-(2-(bromomethyl)-1 H -imidazo[4,5- b ]pyridin-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4 H )-one and thiazol-2-ylmethanamine in place of (7-(4-(3-chloro-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-1-(methylsulfonyl)-1 H- imidazo[4,5- b ]pyridin-2-yl)methyl methanesulfonate and morpholine, respectively.
  • N-(3-chloro-4-fluorophenyl)-2-(thiophen-2-yl)-1H-imidazo[4,5-b]pyridine-7-carboxamide To a soln of the 3-chloro-4-fluoroanilinein (239 mg, 1.64 mmol) dichloroethane at 0 °C under nitrogen was added trimethylaluminum (2 M in heptane, 1.57, 3.15 mmol) dropwise over 5 min. The solution was allowed to warm to room temperature and stirred for 30 min.
  • Example 146 was made analogously to Example 107 using N-(3-chloro-4-fluorophenyl)-2-(thiophen-2-yl)-1H-imidazo[4,5-b]pyridine-7-carboxamide in place of N-(3-Chloro-4-fluorophenyl)-2-methyl-1H-imidazo[4,5-b]pyridine-7-carboxamide.
  • N -(3-chloro-4-fluorophenyl)-2-(pyridin-3-yl)-1 H -imidazo[4,5- b ]pyridine-7-carboxamide A mixture of 2,3-diamino- N -(3-chloro-4-fluorophenyl)isonicotinamide (0.150 g, 0.534 mmol) and nicotinaldehyde (0.50 mL, 5.34 mmol) in DMSO was stirred at 100 °C under air atmosphere for 16 h. Mixture was cooled to rt and diluted with water.
  • Example 147 was synthesized analogously to Example 80, using N -(3-chloro-4-fluorophenyl)-2-(pyridin-3-yl)-1 H -imidazo[4,5- b ]pyridine-7-carboxamide in place of N -(3-bromophenyl)-1 H -imidazo[4,5- b ]pyridine-7-carboxamide.
  • N -(3-chloro-4-fluorophenyl)-2-(1 H -pyrrol-2-yl)-1 H -imidazo[4,5- b ]pyridine-7-carboxamide was synthesized analogously to Example 147 using 1 H -pyrrole-2-carbaldehyde in place of nicotinaldehyde. C 17 H 11 ClFN 5 O. 356.1 [M+1] + .
  • Example 148 was synthesized analogously to Example 80, using N -(3-chloro-4-fluorophenyl)-2-(1 H -pyrrol-2-yl)-1 H -imidazo[4,5- b ]pyridine-7-carboxamide in place of N -(3-bromophenyl)-1 H -imidazo[4,5- b ]pyridine-7-carboxamide.
  • Methyl 2,3-diaminoisonicotinate A mixture of 2,3-diaminoisonicotinic acid (2.0 g, 13 mmol) in sulfuric acid (2.5 mL) and methanol (25 mL) was stirred at 120 °C in a microwave for 1 hr. To the reaction mixture was added aqueous saturated sodium bicarbonate until basic and the aqueous layer was washed three times with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated to give the desired product. C 7 H 9 N 3 O 2 . 168.1 (M+1).
  • Methyl 2-(1H-imidazol-2-yl)-1H-imidazo[4,5-b]pyridine-7-carboxylate was made analogously to Example 147 using methyl 2,3-diaminoisonicotinate and 1H-imidazole-2-carbaldehyde. C 11 H 9 N 5 O 2 . 244.0 (M+1).
  • N-(3-chloro-4-fluorophenyl)-2-(1H-imidazol-2-yl)-1H-imidazo[4,5-b]pyridine-7-carboxamide was made analogously to Example 146 using methyl 2-(1H-imidazol-2-yl)-1H-imidazo[4,5-b]pyridine-7-carboxylate in place of methyl 2-(thiophen-2-yl)-1H-imidazo[4,5-b]pyridine-7-carboxylate.
  • Example 149 was made analogously to Example 107 using N-(3-chloro-4-fluorophenyl)-2-(1H-imidazol-2-yl)-1H-imidazo[4,5-b]pyridine-7-carboxamide in place of N-(3-Chloro-4-fluorophenyl)-2-methyl-1H-imidazo[4,5-b]pyridine-7-carboxamide.
  • Example 150 N -(3-Chloro-4-fluorophenyl)- N' -hydroxy-2-(1 H -pyrazol-5-yl)-1 H- imidazo[4,5- b ]pyridine-7-carboximidamide
  • N -(3-chloro-4-fluorophenyl)-2-(1 H -pyrazol-5-yl)-1 H -imidazo[4,5- b ]pyridine-7-carboxamide was synthesized analogously to Example 147 using 1H-pyrazole-5-carbaldehyde in place of nicotinaldehyde.
  • Example 150 was synthesized analogously to Example 80, using N -(3-chloro-4-fluorophenyl)-2-(1 H -pyrazol-5-yl)-1 H -imidazo[4,5- b ]pyridine-7-carboxamide in place of N -(3-bromophenyl)-1 H -imidazo[4,5- b ]pyridine-7-carboxamide.
  • N -(3-chloro-4-fluorophenyl)- N' -hydroxy-2-(4-methyl-1 H -imidazol-2-yl)-1 H- imidazo[4,5- b ]pyridine-7-carboximidamide To a mixture of N -(3-chloro-4-fluorophenyl)-2-(4-methyl-1 H -imidazol-2-yl)-1 H -imidazo[4,5- b ]pyridine-7-carboxamide (0.009 g, 0.024 mmol) in DCE (0.5 mL) and phosphoryl chloride (0.5 mL) was added phosphorus pentachloride (0.008 g, 0.036 mmol).
  • N-(3-chloro-4-fluorophenyl)-2-cyanamido-3-nitroisonicotinamide A mixture of 2-chloro-N-(3-chloro-4-fluorophenyl)-3-nitroisonicotinamide (1.02 g, 3.09 mmol), cyanamide (260 mg, 6.18 mmol), and potassium carbonate (1.28 g, 9.27 mmol) in dimethylformamide (10 mL) was stirred at 80 °C for 2 hr. The reaction mixture was absorbed onto silica gel and purified by silica gel chromatography to give the desired product (1.03 g). C 13 H 7 ClFN 5 O 3 . 336.0 (M+1).
  • Example 153 was made analogously to Example 107 using 2-amino-N-(3-chloro-4-fluorophenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide in place of N-(3-Chloro-4-fluorophenyl)-2-methyl-1H-imidazo[4,5-b]pyridine-7-carboxamide.
  • N-(3-chloro-4-fluorophenyl)-2-(cyclopropylamino)-1H-imidazo[4,5-b]pyridine-7-carboxamide Dissolved 2,3-diamino-N-(3-chloro-4-fluorophenyl)isonicotinamide (0.54g, 0.002 mol) in THF (5 ml), to the solution was added cyclopropyl isothiocyanate (0.23g, 0.002 mmol) and triethylamine (1.95g, 0.02 mol).
  • Example 154 was made analogously to Example 107 using the general procedure for hydroxyamidine formation. C 16 H 14 ClFN 6 O. 361.1 (M+1).
  • Example 155 was made analogously to Example 154 using phenyl isothiocyanate.
  • Example 156 was made analogously to Example 154 using (2-isothiocyanatoethyl)benzene. C 21 H 18 ClFN 6 O. 425.1 (M+1).
  • Example 157 was made analogously to Example 154 using 1,1,1-trifluoro-2-isothiocyanatoethane.
  • Example 158 was made analogously to Example 154 using methyl isothiocyanate. C 14 H 12 ClFN 6 O. 335.1 (M+1).
  • Example 159 Isopropyl (7-( N -(3-chloro-4-fluorophenyl)- N'- hydroxycarbamimidoyl)-1 H -imidazo[4,5-b]pyridin-2-yl)carbamate
  • Example 159 was made analogously to Example 107 using isopropyl (7-((3-chloro-4-fluorophenyl)carbamoyl)-1H-imidazo[4,5-b]pyridin-2-yl)carbamate in place of N-(3-Chloro-4-fluorophenyl)-2-methyl-1H-imidazo[4,5-b]pyridine-7-carboxamide.
  • Example 160 Ethyl (7-( N -(3-chloro-4-fluorophenyl)- N' -hydroxycarbamimidoyl)-1 H -imidazo[4,5-b]pyridin-2-yl)carbamate
  • Example 160 was made analogously to Example 154 using O-ethyl carbonisothiocyanatidate. C 16 H 14 ClFN 6 O 3 . 393.1 (M+1).

Landscapes

  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Virology (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Neurosurgery (AREA)
  • Psychiatry (AREA)
  • Molecular Biology (AREA)
  • Ophthalmology & Optometry (AREA)
  • Dermatology (AREA)
  • Hospice & Palliative Care (AREA)
  • Pain & Pain Management (AREA)
  • AIDS & HIV (AREA)
  • Transplantation (AREA)
  • Biotechnology (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

Description

    Field
  • The present disclosure relates generally to inhibitors of indoleamine 2,3-dioxygenase 1 (IDO1) activity and their use and manufacture thereof.
    • Background
  • Catabolism of the essential amino acid tryptophan by the inducible heme-containing enzyme indoleamine 2,3-dioxygenase 1 (IDO1) is a central pathway maintaining the immunosuppressive microenvironment in many cancers. IDO1 catalyzes the degradation of tryptophan to kynurenine, and its effects on immune suppression are due to decreased tryptophan availability and the generation of tryptophan metabolites resulting in multipronged negative effects on cytotoxic T lymphocytes, as well as expansion of immunosuppressive regulatory T cells. IDO1 is elevated in multiple cancers, is induced by chemotherapy, targeted therapy, or immunotherapy. IDO1 expression in the tumor microenvironment is correlated with poor prognosis in a variety of cancers. IDO1 inhibitors are positioned to potentiate the efficacy of multiple oncology therapeutics including immunotherapies, targeted agents, and chemotherapies. Indeed, epacadostat (INCB24360), a potent and selective IDO1 inhibitor, entered clinical trials and is demonstrating activity in combination with ipilimumab (anti-CTLA4) in melanoma.
  • In addition to the above, IDO1 has been shown to play a role in chronic infections, HIV and AIDS, autoimmune diseases or disorders (e.g., rheumatoid arthritis), and immunologic tolerance, prevention of fetal rejection in utero. Inhibition of IDO1 may also be an important treatment strategy for patients with neurological or neuropsychiatric diseases or disorders, such as depression.
  • WO2015/002918 and WO2014/159248 disclose heteroaryl compounds having activity as inhibitors of indoleamine 2,3-dioxygenase.
  • A need remains for additional therapeutic agents useful to treat proliferative disorders or diseases that are mediated by IDO1.
    • Summary
  • The present disclosure provides compounds that function as inhibitors of IDO1. The disclosure also provides compositions, including pharmaceutical compositions, kits that include the compounds, and methods of making the compounds. The compounds provided herein are useful in treating diseases, disorders, or conditions that are mediated by IDO1. The disclosure also provides compounds for use in therapy. The disclosure further provides compounds for use in a method of treating a disease, disorder, or condition that is mediated by IDO1. Moreover, the disclosure provides uses of the compounds in the manufacture of a medicament for the treatment of a disease, disorder or condition that is mediated by IDO1.
  • In one aspect, provided is a compound having the structure of Formula I:
    Figure imgb0001
     wherein
    • R1 is mono or bicyclic aryl or heteroaryl, wherein each mono or bicyclic aryl or heteroaryl is optionally substituted with one, two, or three substituents independently selected from hydroxyl, halo, -CN, C1-6 haloalkyl, C1-6 haloalkoxy, C1-6 alkoxy, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C3-6 cycloalkyl, wherein two of the optional substituents can join to form an additional partially saturated heterocyclic ring; and
      wherein each C1-6 alkoxy, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C3-6 cycloalkyl is optionally substituted with one, two, or three substituents independently selected from hydroxyl, halo, -CN, - N(R20)(R22) and C3-6 cycloalkyl;
    • X is N or CR2c;
    • R2a, R2b, and R2c are independently hydrogen, hydroxyl, halo, CN, C1-6 haloalkyl, C1-6 haloalkoxy, C1-6 alkoxy, or C1-6 alkyl;
    • R2d and R2e are independently hydrogen, C1-6 haloalkyl, C1-6 haloalkoxy, or C1-6 alkyl;
    • n and m are independently 0, 1, 2, or 3;
    • each Rn and Rm are independently hydrogen, hydroxyl, halo, C1-6 alkoxy, C1-6 alkyl, C3-6 cycloalkyl, aryl, heterocyclyl, or heteroaryl; or two Rn or Rm join to form a C3-6 cycloalkyl; and
      wherein each C1-6 alkoxy, C1-6 alkyl, C3-6 cycloalkyl aryl, heterocyclyl, or heteroaryl is optionally substituted with one, two, or three substituents independently selected from hydroxyl, halo, -CN, - N(R20)(R22), C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 haloalkoxy, C1-6 alkoxy, C1-6 alkyl, and C3-6 cycloalkyl;
    • L is a bond, -NR3-, -C(O)-NR3-, -NR3-C(O)-, -NR3SO2-, -NR3SO2-NR3-,-SO2NR3-, -O-, -S-, or -S(O)t-, where t is 0, 1 or 2;
    • each R3 is independently hydrogen, C1-6 alkyl, C3-6 cycloalkyl, aryl, heterocyclyl, or heteroaryl; and
    • Rt is hydrogen, C1-6 alkyl, C1-6 alkoxy, -C(O)R20, -C(O)OR20, -NC(O)OR20,-N(R20)(R22), -C(O)N(R20)(R22), -SO2R20, -N(R20)SO2(R21), -N(R20)SO2-N(R21)(R22), -SO2N(R20)(R22), C3-15 cycloalkyl, aryl, heteroaryl, or heterocyclyl, provided that when Rt is C1-6 alkoxy, -NC(O)OR20,-N(R20)(R22), -N(R20)SO2(R21), -N(R20)SO2-N(R21)(R22), or - SO2N(R20)(R22), and m is 0, then L is a bond;
      wherein said C1-6 alkyl, C1-6 alkoxy, C3-15 cycloalkyl, aryl, heterocyclyl, or heteroaryl is optionally substituted with one, two, or three substituents independently selected from hydroxyl, halo, -NO2, C1-6 haloalkyl, C1-6 haloalkoxy, -C(O)R20, -N(R20)(R22), -SO2R20,-N(R20)SO2(R21), -N(R20)SO2-N(R21)(R22), -SO2N(R20)(R22), C3-6 cycloalkyl, -CN, C1-6 alkoxy, C1-6 alkyl, and heterocyclyl; and wherein said heterocyclyl is optionally substituted with one or two oxo;
      wherein said C3-6 cycloalkyl, C1-6 alkyl or C1-6 alkoxy is optionally substituted with one, two, or three substituents independently selected from hydroxyl, halo, -NO2, C1-6 haloalkyl, C1-6 haloalkoxy, C1-6 alkoxy, - N(R20)(R22), -SO2R20, -N(R20)SO2(R22), -N(R20)SO2-N(R21)(R22)-, and -SO2N(R20)(R22); and said C1-6 alkyl is optionally substituted with aryl;
    • R20, R21, and R22 are independently selected from hydrogen, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, aryl, heterocyclyl, and heteroaryl; wherein said aryl, heterocyclyl, or heteroaryl is optionally substituted with one, two, or three halogen;
    or a pharmaceutically acceptable salt, or mixture thereof.
  • Some embodiments provide the compounds of formula I for use in the treatment of a disease or condition in a mammal, particularly a human, that is amenable to treatment by an IDO1 inhibitor.
  • In certain embodiments, the disclosure provides pharmaceutical compositions comprising a therapeutically effective amount of a compound of the disclosure (e.g. a compound of Formula I), and at least one pharmaceutically acceptable excipient.
  • The inventions of this disclosure are described throughout. In addition, specific embodiments of the invention are as disclosed herein.
    • Detailed Description Definitions and General Parameters
  • The following description sets forth exemplary methods, parameters and the like. It should be recognized, however, that such description is not intended as a limitation on the scope of the present disclosure but is instead provided as a description of exemplary embodiments.
  • As used in the present specification, the following words, phrases and symbols are generally intended to have the meanings as set forth below, except to the extent that the context in which they are used indicates otherwise.
  • A dash ("-") that is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, -CONH2 is attached through the carbon atom. A dash at the front or end of a chemical group is a matter of convenience; chemical groups may be depicted with or without one or more dashes without losing their ordinary meaning. A wavy line drawn through a line in a structure indicates a point of attachment of a group. Unless chemically or structurally required, no directionality is indicated or implied by the order in which a chemical group is written or named.
  • The prefix "Cu-v" indicates that the following group has from u to v carbon atoms. For example, "C1-6 alkyl" indicates that the alkyl group has from 1 to 6 carbon atoms.
  • Reference to "about" a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se. In certain embodiments, the term "about" includes the indicated amount ± 10%. In other embodiments, the term "about" includes the indicated amount ± 5%. In certain other embodiments, the term "about" includes the indicated amount ± 1%. Also, to the term "about X" includes description of "X". Also, the singular forms "a" and "the" include plural references unless the context clearly dictates otherwise. Thus, e.g., reference to "the compound" includes a plurality of such compounds and reference to "the assay" includes reference to one or more assays and equivalents thereof known to those skilled in the art.
  • "Alkyl" refers to an unbranched or branched saturated hydrocarbon chain. As used herein, alkyl has 1 to 20 carbon atoms (i.e., C1-20 alkyl), 1 to 8 carbon atoms (i.e., C1-8 alkyl), 1 to 6 carbon atoms (i.e., C1-6 alkyl), or 1 to 4 carbon atoms (i.e., C1-4 alkyl). Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. When an alkyl residue having a specific number of carbons is named by chemical name or identified by molecular formula, all positional isomers having that number of carbons may be encompassed; thus, for example, "butyl" includes n-butyl (i.e. -(CH2)3CH3), sec-butyl (i.e. -CH(CH3)CH2CH3), isobutyl (i.e.-CH2CH(CH3)2) and tert-butyl (i.e. -C(CH3)3); and "propyl" includes n-propyl (i.e.-(CH2)2CH3) and isopropyl (i.e. -CH(CH3)2).
  • "Alkenyl" refers to an aliphatic group containing at least one carbon-carbon double bond and having from 2 to 20 carbon atoms (i.e., C2-20 alkenyl), 2 to 8 carbon atoms (i.e., C2-8 alkenyl), 2 to 6 carbon atoms (i.e., C2-6 alkenyl), or 2 to 4 carbon atoms (i.e., C2-4 alkenyl). Examples of alkenyl groups include ethenyl, propenyl, butadienyl (including 1,2-butadienyl and 1,3-butadienyl).
  • "Alkynyl" refers to an aliphatic group containing at least one carbon-carbon triple bond and having from 2 to 20 carbon atoms (i.e., C2-20 alkynyl), 2 to 8 carbon atoms (i.e., C2-8 alkynyl), 2 to 6 carbon atoms (i.e., C2-6 alkynyl), or 2 to 4 carbon atoms (i.e., C2-4 alkynyl). The term "alkynyl" also includes those groups having one triple bond and one double bond.
  • "Alkoxy" refers to the group "alkyl-O-". Examples of alkoxy groups include methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy. "Haloalkoxy" refers to an alkoxy group as defined above, wherein one or more hydrogen atoms are replaced by a halogen.
  • "Acyl" refers to a group -C(=O)R, wherein R is hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein. Examples of acyl include formyl, acetyl, cylcohexylcarbonyl, cyclohexylmethyl-carbonyl, and benzoyl.
  • "Amido" refers to both a "C-amido" group which refers to the group - C(=O)NRyRz and an "N-amido" group which refers to the group -NRyC(=O)Rz, wherein Ry and Rz are independently selected from the group consisting of hydrogen, alkyl, aryl, haloalkyl, or heteroaryl; each of which may be optionally substituted.
  • "Amino" refers to the group -NRyRz wherein Ry and Rz are independently selected from the group consisting of hydrogen, alkyl, haloalkyl, aryl, or heteroaryl; each of which may be optionally substituted.
  • "Aryl" refers to an aromatic carbocyclic group having a single ring (e.g. monocyclic) or multiple rings (e.g. bicyclic or tricyclic) including fused systems. As used herein, aryl has 6 to 20 ring carbon atoms (i.e., C6-20 aryl), 6 to 12 carbon ring atoms (i.e., C6-2 aryl), or 6 to 10 carbon ring atoms (i.e., C6-10 aryl). Examples of aryl groups include phenyl, naphthyl, fluorenyl, and anthryl. Aryl, however, does not encompass or overlap in any way with heteroaryl defined below. If one or more aryl groups are fused with a heteroaryl ring, the resulting ring system is heteroaryl.
  • "Cyano" or "carbonitrile" refers to the group -CN.
  • "Cycloalkyl" refers to a saturated or partially saturated cyclic alkyl group having a single ring or multiple rings including fused, bridged, and spiro ring systems. The term "cycloalkyl" includes cycloalkenyl groups (i.e. the cyclic group having at least one double bond). As used herein, cycloalkyl has from 3 to 20 ring carbon atoms (i.e., C3-20 cycloalkyl), 3 to 12 ring carbon atoms (i.e., C3-12 cycloalkyl), 3 to 10 ring carbon atoms (i.e., C3-10 cycloalkyl), 3 to 8 ring carbon atoms (i.e., C3-8 cycloalkyl), or 3 to 6 ring carbon atoms (i.e., C3-6 cycloalkyl). Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • "Halogen" or "halo" includes fluoro, chloro, bromo, and iodo. "Haloalkyl" refers to an unbranched or branched alkyl group as defined above, wherein one or more hydrogen atoms are replaced by a halogen. For example, where a residue is substituted with more than one halogen, it may be referred to by using a prefix corresponding to the number of halogen moieties attached. Dihaloalkyl and trihaloalkyl refer to alkyl substituted with two ("di") or three ("tri") halo groups, which may be, but are not necessarily, the same halogen. Examples of haloalkyl include difluoromethyl (-CHF2) and trifluoromethyl (-CF3).
  • "Heteroalkyl" refers to an alkyl group in which one or more of the carbon atoms (and any associated hydrogen atoms) are each independently replaced with the same or different heteroatomic group. The term "heteroalkyl" includes unbranched or branched saturated chain having carbon and heteroatoms. By way of example, 1, 2 or 3 carbon atoms may be independently replaced with the same or different heteroatomic group. Heteroatomic groups include, but are not limited to, -NR-, -O-, -S-, -S(O)-, - S(O)2-, and the like, where R is H, alkyl, aryl, cycloalkyl, heteroalkyl, heteroaryl or heterocyclyl, each of which may be optionally substituted. Examples of heteroalkyl groups include -OCH3, -CH2OCH3, -SCH3, -CH2SCH3, -NRCH3, and -CH2NRCH3, where R is hydrogen, alkyl, aryl, arylalkyl, heteroalkyl, or heteroaryl, each of which may be optionally substituted. As used herein, heteroalkyl include 1 to 10 carbon atoms, 1 to 8 carbon atoms, or 1 to 4 carbon atoms; and 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom.
  • "Heteroaryl" refers to an aromatic group having a single ring, multiple rings, or multiple fused rings, with one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. As used herein, heteroaryl include 1 to 20 ring carbon atoms (i.e., C1-20 heteroaryl), 3 to 12 ring carbon atoms (i.e., C3-12 heteroaryl), or 3 to 8 carbon ring atoms (i.e., C3-8 heteroaryl); and 1 to 5 heteroatoms, 1 to 4 heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, oxygen, and sulfur. Examples of heteroaryl groups include pyrimidinyl, purinyl, pyridyl, pyridazinyl, benzothiazolyl, and pyrazolyl. Heteroaryl does not encompass or overlap with aryl as defined above.
  • "Heterocyclyl" or "heterocyclic ring" refers to an unsaturated non-aromatic cyclic alkyl group, with one or more ring heteroatoms independently selected from nitrogen, oxygen and sulfur. As used herein, "heterocyclyl" or "heterocyclic ring" refers to rings that are saturated or partially saturated unless otherwise indicated, e.g., in some embodiments "heterocyclyl" or "heterocyclic ring" refers to rings that are partially saturated where specified. The term "heterocyclyl" or "heterocyclic ring" includes heterocycloalkenyl groups (i.e., the heterocyclyl group having at least one double bond). A heterocyclyl may be a single ring or multiple rings wherein the multiple rings may be fused, bridged, or spiro. As used herein, heterocyclyl has 2 to 20 ring carbon atoms (i.e., C2-20 heterocyclyl), 2 to 12 ring carbon atoms (i.e., C2-12 heterocyclyl), 2 to 10 ring carbon atoms (i.e., C2-10 heterocyclyl), 2 to 8 ring carbon atoms (i.e., C2-8 heterocyclyl), 3 to 12 ring carbon atoms (i.e., C3-12 heterocyclyl), 3 to 8 ring carbon atoms (i.e., C3-8 heterocyclyl), or 3 to 6 ring carbon atoms (i.e., C3-6 heterocyclyl); having 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, sulfur or oxygen. Examples of heterocyclyl groups include pyrrolidinyl, piperidinyl, piperazinyl, oxetanyl, dioxolanyl, azetidinyl, and morpholinyl. As used herein, the term "bridged- heterocyclyl" refers to a four- to ten-membered cyclic moiety connected at two non-adjacent atoms of the heterocyclyl with one or more (e.g., 1 or 2) four- to ten-membered cyclic moiety having at least one heteroatom where each heteroatom is independently selected from nitrogen, oxygen, and sulfur. As used herein, "bridged-heterocyclyl" includes bicyclic and tricyclic ring systems. Also as used herein, the term "spiro-heterocyclyl" refers to a ring system in which a three- to ten-membered heterocyclyl has one or more additional ring, wherein the one or more additional ring is three- to ten-membered cycloalkyl or three- to ten-membered heterocyclyl, where a single atom of the one or more additional ring is also an atom of the three- to ten-membered heterocyclyl. Examples of the spiro-heterocyclyl include bicyclic and tricyclic ring systems, such as 2-oxa-7-azaspiro[3.5]nonanyl, 2-oxa-6-azaspiro[3.4]octanyl, and 6-oxa-1-azaspiro[3.3]heptanyl.
  • "Hydroxy" or "hydroxyl" refers to the group -OH.
  • "Oxo" refers to the group (=O) or (O).
  • "Sulfonyl" refers to the group -S(O)2R, where R is alkyl, haloalkyl, heterocyclyl, cycloalkyl, heteroaryl, or aryl. Examples of sulfonyl are methylsulfonyl, ethylsulfonyl, phenylsulfonyl, and toluenesulfonyl.
  • Certain commonly used alternative chemical names may be used. For example, a divalent group such as a divalent "alkyl" group, a divalent "aryl" group, etc., may also be referred to as an "alkylene" group or an "alkylenyl" group, an "arylene" group or an "arylenyl" group, respectively. Also, unless indicated explicitly otherwise, where combinations of groups are referred to herein as one moiety, e.g. arylalkyl, the last mentioned group contains the atom by which the moiety is attached to the rest of the molecule.
  • The terms "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not. Also, the term "optionally substituted" refers to any one or more hydrogen atoms on the designated atom or group may or may not be replaced by a moiety other than hydrogen.
  • The term "substituted" means that any one or more hydrogen atoms on the designated atom or group is replaced with one or more substituents other than hydrogen, provided that the designated atom's normal valence is not exceeded. The one or more substituents include, but are not limited to, alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amido, amidino, aryl, azido, carbamoyl, carboxyl, carboxyl ester, cyano, guanidino, halo, haloalkyl, heteroalkyl, heteroaryl, heterocyclyl, hydroxy, hydrazino, imino, oxo, nitro, alkylsulfinyl, sulfonic acid, alkylsulfonyl, thiocyanate, thiol, thione, or combinations thereof. Polymers or similar indefinite structures arrived at by defining substituents with further substituents appended ad infinitum (e.g., a substituted aryl having a substituted alkyl which is itself substituted with a substituted aryl group, which is further substituted by a substituted heteroalkyl group, etc.) are not intended for inclusion herein. Unless otherwise noted, the maximum number of serial substitutions in compounds described herein is three. For example, serial substitutions of substituted aryl groups with two other substituted aryl groups are limited to ((substituted aryl)substituted aryl) substituted aryl. Similarly, the above definitions are not intended to include impermissible substitution patterns (e.g., methyl substituted with 5 fluorines or heteroaryl groups having two adjacent oxygen ring atoms). Such impermissible substitution patterns are well known to the skilled artisan. When used to modify a chemical group, the term "substituted" may describe other chemical groups defined herein. For example, the term "substituted aryl" includes, but is not limited to, "alkylaryl." Unless specified otherwise, where a group is described as optionally substituted, any substituents of the group are themselves unsubstituted.
  • In some embodiments, the term "substituted alkyl" refers to an alkyl group having one or more substituents including hydroxyl, halo, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl. In additional embodiments, "substituted cycloalkyl" refers to a cycloalkyl group having one or more substituents including alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, halo, oxo, and hydroxyl; "substituted heterocyclyl" refers to a heterocyclyl group having one or more substituents including alkyl, haloalkyl, heterocyclyl, cycloalkyl, aryl, heteroaryl, alkoxy, halo, oxo, and hydroxyl; "substituted aryl" refers to an aryl group having one or more substituents including halo, alkyl, haloalkyl, cycloalkyl, heterocyclyl, heteroaryl, alkoxy, and cyano; "substituted heteroaryl" refers to an heteroaryl group having one or more substituents including halo, alkyl, haloalkyl, heterocyclyl, heteroaryl, alkoxy, and cyano and "substituted sulfonyl" refers to a group -S(O)2R, in which R is substituted with one or more substituents including alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl. In other embodiments, the one or more substituents may be further substituted with halo, alkyl, haloalkyl, hydroxyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is substituted. In other embodiments, the substituents may be further substituted with halo, alkyl, haloalkyl, alkoxy, hydroxyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is unsubstituted.
  • Some of the compounds exist as tautomeric isomers. Tautomeric isomers are in equilibrium with one another. For example, amide containing compounds may exist in equilibrium with imidic acid tautomers. Regardless of which tautomer is shown, and regardless of the nature of the equilibrium among tautomers, the compounds are understood by one of ordinary skill in the art to comprise both amide and imidic acid tautomers. Thus, the amide containing compounds are understood to include their imidic acid tautomers. Likewise, the imidic acid containing compounds are understood to include their amide tautomers.
  • Any formula or structure given herein, is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds. Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as, but not limited to 2H (deuterium, D), 3H (tritium), 11C, 13C, 14C, 15N, 18 F, 31P, 32P, 35S, 36Cl and 125I. Various isotopically labeled compounds of the present disclosure, for example those into which radioactive isotopes such as 3H, 13C and 14C are incorporated. Such isotopically labelled compounds may be useful in metabolic studies, reaction kinetic studies, detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays or in radioactive treatment of patients.
  • The disclosure also included compounds of Formula I in which from 1 to n hydrogens attached to a carbon atom is/are replaced by deuterium, in which n is the number of hydrogens in the molecule. Such compounds exhibit increased resistance to metabolism and are thus useful for increasing the half-life of any compound of Formula I when administered to a mammal, particularly a human. See, for example, Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism," Trends Pharmacol. Sci. 5(12):524-527 (1984). Such compounds are synthesized by means well known in the art, for example by employing starting materials in which one or more hydrogens have been replaced by deuterium.
  • Deuterium labelled or substituted therapeutic compounds of the disclosure may have improved DMPK (drug metabolism and pharmacokinetics) properties, relating to distribution, metabolism and excretion (ADME). Substitution with heavier isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life, reduced dosage requirements and/or an improvement in therapeutic index. An 18F labeled compound may be useful for PET or SPECT studies. Isotopically labeled compounds of this disclosure and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent. It is understood that deuterium in this context is regarded as a substituent in the compound of Formula I.
  • The concentration of such a heavier isotope, specifically deuterium, may be defined by an isotopic enrichment factor. In the compounds of this disclosure any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom. Unless otherwise stated, when a position is designated specifically as "H" or "hydrogen", the position is understood to have hydrogen at its natural abundance isotopic composition. Accordingly, in the compounds of this disclosure any atom specifically designated as a deuterium (D) is meant to represent deuterium.
  • In many cases, the compounds of this disclosure are capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto.
  • The term "pharmaceutically acceptable salt" of a given compound refers to salts that retain the biological effectiveness and properties of the given compound, and which are not biologically or otherwise undesirable. Pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. Salts derived from inorganic bases include, by way of example only, sodium, potassium, lithium, ammonium, calcium and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines, such as alkyl amines, dialkyl amines, trialkyl amines, substituted alkyl amines, di(substituted alkyl) amines, tri(substituted alkyl) amines, alkenyl amines, dialkenyl amines, trialkenyl amines, substituted alkenyl amines, di(substituted alkenyl) amines, tri(substituted alkenyl) amines, mono, di or tri cycloalkyl amines, mono, di or tri arylamines or mixed amines, etc. Specific examples of suitable amines include, by way of example only, isopropylamine, trimethyl amine, diethyl amine, tri(iso-propyl) amine, tri(n-propyl) amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like.
  • Pharmaceutically acceptable acid addition salts may be prepared from inorganic and organic acids. Salts derived from inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Salts derived from organic acids include acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluene-sulfonic acid, salicylic acid, and the like.
  • As used herein, "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions.
  • "Treatment" or "treating" is an approach for obtaining beneficial or desired results including clinical results. Beneficial or desired clinical results may include one or more of the following: a) inhibiting the disease or condition (e.g., decreasing one or more symptoms resulting from the disease or condition, and/or diminishing the extent of the disease or condition); b) slowing or arresting the development of one or more clinical symptoms associated with the disease or condition (e.g., stabilizing the disease or condition, preventing or delaying the worsening or progression of the disease or condition, and/or preventing or delaying the spread (e.g., metastasis) of the disease or condition); and/or c) relieving the disease, that is, causing the regression of clinical symptoms (e.g., ameliorating the disease state, providing partial or total remission of the disease or condition, enhancing effect of another medication, delaying the progression of the disease, increasing the quality of life, and/or prolonging survival.
  • "Prevention" or "preventing" means any treatment of a disease or condition that causes the clinical symptoms of the disease or condition not to develop. Compounds may, in some embodiments, be administered to a subject (including a human) who is at risk or has a family history of the disease or condition.
  • "Subject" refers to an animal, such as a mammal (including a human), that has been or will be the object of treatment, observation or experiment. The methods described herein may be useful in human therapy and/or veterinary applications. In some embodiments, the subject is a mammal. In one embodiment, the subject is a human.
  • The term "therapeutically effective amount" or "effective amount" of a compound described herein or pharmaceutically acceptable salts, isomer, or a mixture thereof means an amount sufficient to effect treatment when administered to a subject, to provide a therapeutic benefit such as amelioration of symptoms or slowing of disease progression. For example, a therapeutically effective amount may be an amount sufficient to decrease a symptom of a disease or condition responsive to inhibition of IDO1 activity. The therapeutically effective amount may vary depending on the subject, and disease or condition being treated, the weight and age of the subject, the severity of the disease or condition, and the manner of administering, which can readily be determined by one or ordinary skill in the art.
  • The term "inhibition" indicates a decrease in the baseline activity of a biological activity or process. "Inhibition of activity of IDO1" or variants thereof refers to a decrease in activity in IDO1 as a direct or indirect response to the presence of a compound of the present application relative to the activity IDO1 in the absence of the compound of the present application. "Inhibition of IDO1" refers to a decrease in IDO1 activity as a direct or indirect response to the presence of a compound described herein relative to the activity of IDO1 in the absence of the compound described herein. In some embodiments, the inhibition of IDO1 activity may be compared in the same subject prior to treatment, or other subjects not receiving the treatment.
    • Compounds
  • Provided herein are compounds that function as inhibitors of IDO1. In one aspect, provided is a compound having structure of Formula I:
    Figure imgb0002
     wherein
    • R1 is mono or bicyclic aryl or heteroaryl, wherein each mono or bicyclic aryl or heteroaryl is optionally substituted with one, two, or three substituents independently selected from hydroxyl, halo, -CN, C1-6 haloalkyl, C1-6 haloalkoxy, C1-6 alkoxy, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C3-6 cycloalkyl, wherein two of the optional substituents can join to form an additional partially saturated heterocyclic ring; and
      wherein each C1-6 alkoxy, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C3-6 cycloalkyl is optionally substituted with one, two, or three substituents independently selected from hydroxyl, halo, -CN,-N(R20)(R22) and C3-6 cycloalkyl;
    • X is N or CR2c;
    • R2a, R2b, and R2c are independently hydrogen, hydroxyl, halo, CN, C1-6 haloalkyl, C1-6 haloalkoxy, C1-6 alkoxy, or C1-6 alkyl;
    • R2d and R2e are independently hydrogen, C1-6 haloalkyl, C1-6 haloalkoxy, or C1-6 alkyl;
    • n and m are independently 0, 1, 2, or 3;
    • each Rn and Rm are independently hydrogen, hydroxyl, halo, C1-6 alkoxy, C1-6 alkyl, C3-6 cycloalkyl, aryl, heterocyclyl, or heteroaryl; or two Rn or Rm join to form a C3-6 cycloalkyl; and
      wherein each C1-6 alkoxy, C1-6 alkyl, C3-6 cycloalkyl aryl, heterocyclyl, or heteroaryl is optionally substituted with one, two, or three substituents independently selected from hydroxyl, halo, -CN,-N(R20)(R22), C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 haloalkoxy, C1-6 alkoxy, C1-6 alkyl, and C3-6 cycloalkyl;
    • L is a bond, -NR3-, -C(O)-NR3-, -NR3-C(O)-, -NR3SO2-, -NR3SO2-NR3-,-SO2NR3-, -O-, -S-, or -S(O)t-, where t is 0, 1 or 2;
    • each R3 is independently hydrogen, C1-6 alkyl, C3-6 cycloalkyl, aryl, heterocyclyl, or heteroaryl; and
    • Rt is hydrogen, C1-6 alkyl, C1-6 alkoxy, -C(O)R20, -C(O)OR20, -NC(O)OR20,-N(R20)(R22), -C(O)N(R20)(R22), -SO2R20, -N(R20)SO2(R21), -N(R20)SO2-N(R21)(R22), -SO2N(R20)(R22), C3-15 cycloalkyl, aryl, heteroaryl, or heterocyclyl, provided that when Rt is C1-6 alkoxy, -NC(O)OR20,-N(R20)(R22), -N(R20)SO2(R21), -N(R20)SO2-N(R21)(R22), or-SO2N(R20)(R22), and m is 0, then L is a bond;
      wherein said C1-6 alkyl, C1-6 alkoxy, C3-15 cycloalkyl, aryl, heterocyclyl, or heteroaryl is optionally substituted with one, two, or three substituents independently selected from hydroxyl, halo, -NO2, C1-6 haloalkyl, C1-6 haloalkoxy, -C(O)R20, -N(R20)(R22), -SO2R20,-N(R20)SO2(R21), -N(R20)SO2-N(R21)(R22), -SO2N(R20)(R22), C3-6 cycloalkyl, -CN, C1-6 alkoxy, C1-6 alkyl, and heterocyclyl; and wherein said heterocyclyl is optionally substituted with one or two oxo;
      wherein said C3-6 cycloalkyl, C1-6 alkyl or C1-6 alkoxy is optionally substituted with one, two, or three substituents independently selected from hydroxyl, halo, -NO2, C1-6 haloalkyl, C1-6 haloalkoxy, C1-6 alkoxy,-N(R20)(R22), -SO2R21, -N(R20)SO2(R22), -N(R20)SO2-N(R21)(R22)-, and -SO2N(R20)(R22); and said C1-6 alkyl is optionally substituted with aryl;
    • R20, R21, and R22 are independently selected from hydrogen, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, aryl, heterocyclyl, and heteroaryl; wherein said aryl, heterocyclyl, or heteroaryl is optionally substituted with one, two, or three halogen;
    or a pharmaceutically acceptable salt, or mixture thereof.
  • In some embodiments, R1 is bicyclic aryl or heteroaryl optionally substituted with one, two, or three substituents independently selected from hydroxyl, halo, -CN, C1-6 haloalkyl, C1-6 haloalkoxy, C1-6 alkoxy, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C3-6 cycloalkyl, wherein two of the optional substituents can join to form an additional partially saturated heterocyclic ring; and wherein each C1-6 alkoxy, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C3-6 cycloalkyl is optionally substituted with one, two, or three substituents independently selected from hydroxyl, halo, -CN, -N(R20)(R22), and C3-6 cycloalkyl.
  • In some embodiments, R1 is bicyclic aryl or heteroaryl optionally substituted with one, two, or three substituents independently selected from hydroxyl, halo, -CN, C1-6 haloalkyl, C1-6 haloalkoxy, C1-6 alkoxy, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C3-6 cycloalkyl.
  • In some embodiments, the compound is selected from the group consisting of:
    • N'-hydroxy-N-naphthalen-2-yl-1H-imidazo[4,5-b]pyridine-7-carboximidamide;
    • N'-hydroxy-N-naphthalen-1-yl-1H-imidazo[4,5-b]pyridine-7-carboximidamide;
    • N-(4-chloronaphthalen-1-yl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide;
    • N-(3-chloronaphthalen-2-yl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide;
    • N-(1-benzofuran-4-yl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide;
    • N-(1-benzofuran-6-yl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide;
    • N-(1-benzofuran-7-yl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide; and
    • N-(1-benzofuran-5-yl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide.
  • In some embodiments, R1 is phenyl optionally substituted with one, two, or three substituents independently selected from hydroxyl, halo, -CN, C1-6 haloalkyl, C1-6 haloalkoxy, C1-6 alkoxy, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C3-6 cycloalkyl, wherein two of the optional substituents can join to form an additional partially saturated heterocyclic ring; and wherein each C1-6 alkoxy, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C3-6 cycloalkyl is optionally substituted with one, two, or three substituents independently selected from hydroxyl, halo, -CN, -N(R20)(R22), and C3-6 cycloalkyl.
  • In some embodiments, R1 is phenyl optionally substituted with one, two, or three substituents independently selected from hydroxyl, halo, -CN, -CHF2, -O-CHF2, -CF3, -O-CF3, C1-4 alkoxy, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, and C3-6 cycloalkyl, and wherein two of the optional substituents can join to form an additional partially saturated heterocyclic ring.
  • In some embodiments, at least one of R2a, R2b, and, when present, R2c are not hydrogen. In some embodiments, R2a is not hydrogen. In some embodiments, R2b is not hydrogen. In some embodiments, R2c is not hydrogen.
  • In some embodiments, the compound is selected from the group consisting of:
    • N-(3-chloro-4-fluorophenyl)-6-fluoro-N'-hydroxy-1H-benzimidazole-4-carboximidamide;
    • N-(3-chloro-4-fluorophenyl)-7-fluoro-N'-hydroxy-3H-benzimidazole-4-carboximidamide;
    • 7-chloro-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-3H-benzimidazole-4-carboximidamide;
    • N-(3-chloro-4-fluorophenyl)-N'-hydroxy-7-(trifluoromethyl)-1H-benzimidazole-4-carboximidamide;
    • N-(3-chloro-4-fluorophenyl)-6,7-difluoro-N'-hydroxy-2-(2-morpholin-4-ylethylamino)-3H-benzimidazole-4-carboximidamide;
    • N-(3-chloro-4-fluorophenyl)-6,7-difluoro-N'-hydroxy-2-(methylaminomethyl)-1H-benzimidazole-4-carboximidamide;
    • N-(3-chloro-4-fluorophenyl)-6-fluoro-N'-hydroxy-7-methyl-3H-benzimidazole-4-carboximidamide;
    • N-(3-chloro-4-fluorophenyl)-N'-hydroxy-7-methyl-3H-benzimidazole-4-carboximidamide;
    • N-(3-chloro-4-fluorophenyl)-6,7-difluoro-N'-hydroxy-3H-benzimidazole-4-carboximidamide;
    • N-(3-chloro-4-fluorophenyl)-N'-hydroxy-7-(trifluoromethoxy)-3H-benzimidazole-4-carboximidamide; and
    • N-(3-chloro-4-fluorophenyl)-5-fluoro-N'-hydroxy-3H-benzimidazole-4-carboximidamide.
  • In some embodiments, L is a bond.
  • In some embodiments, Rt is C1-6 alkyl optionally substituted with one, two, or three substituents independently selected from hydroxyl, halo, -NO2, C1-6 haloalkyl, C1-6 haloalkoxy, C3-6 cycloalkyl, -CN, and C1-6 alkoxy.
  • In some embodiments, the compound is selected from the group consisting of:
    • N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(methoxymethyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide;
    • N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(2-hydroxyethyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide;
    • 2-(chloromethyl)-N-[4-fluoro-3-(trifluoromethyl)phenyl]-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide;
    • N-[4-fluoro-3-(trifluoromethyl)phenyl]-N'-hydroxy-2-(hydroxymethyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide;
    • N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(hydroxymethyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide;
    • N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(1-hydroxyethyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide;
    • N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(2,2,2-trifluoro-1-hydroxyethyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide;
    • N-(3-chloro-4-fluorophenyl)-2-[cyclopropyl(hydroxy)methyl]-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide;
    • N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(2-hydroxypropan-2-yl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide; and
    • 2-(aminomethyl)-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide.
  • In some embodiments, Rt is C3-15 cycloalkyl, aryl, heteroaryl, or heterocyclyl, wherein said cycloalkyl, aryl, heterocyclyl, or heteroaryl is optionally substituted with one, two, or three substituents independently selected from hydroxyl, halo, -NO2, C1-6 haloalkyl, C1-6 haloalkoxy, C3-6 cycloalkyl, -CN, C1-6 alkoxy and C1-6 alkyl.
  • In some embodiments, the compound is selected from the group consisting of:
    • N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(2-morpholin-4-ylethyl)-3H-imidazo[4,5-b]pyridine-7-carboximidamide;
    • N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(pyrrolidin-1-ylmethyl)-3H-imidazo[4,5-b]pyridine-7-carboximidamide;
    • N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(piperidin-1-ylmethyl)-3H-imidazo[4,5-b]pyridine-7-carboximidamide;
    • N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-pyridin-3-yl-1H-imidazo[4,5-b]pyridine-7-carboximidamide;
    • N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(1H-pyrrol-2-yl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide;
    • N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-[(2S)-pyrrolidin-2-yl]-1H-imidazo[4,5-b]pyridine-7-carboximidamide;
    • N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(1H-pyrazol-5-yl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide;
    • N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(1H-imidazol-2-yl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide;
    • N-(3-chloro-4-fluorophenyl)-2-cyclopropyl-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide;
    • N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-thiophen-2-yl-3H-imidazo[4,5-b]pyridine-7-carboximidamide;
    • N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(morpholin-4-ylmethyl)-3H-imidazo[4,5-b]pyridine-7-carboximidamide;
    • N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-[hydroxy(phenyl)methyl]-1H-imidazo[4,5-b]pyridine-7-carboximidamide;
    • N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-methyl-1H-imidazo[4,5-b]pyridine-7-carboximidamide;
    • N-(3-chloro-4-fluorophenyl)-2-ethyl-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide;
    • N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(2-piperidin-1-ylethyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide;
    • N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(2-pyrrolidin-1-ylethyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide; and
    • N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(5-methyl-1H-imidazol-2-yl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide.
  • In some embodiments, Rt is hydrogen.
  • In some embodiments, the compound is selected from the group consisting of:
    • N-(3-ethynylphenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide;
    • N-(3-ethynyl-4-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide;
    • N-[3-(difluoromethyl)phenyl]-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide;
    • N'-hydroxy-N-[3-(trifluoromethoxy)phenyl]-1H-imidazo[4,5-b]pyridine-7-carboximidamide;
    • N'-hydroxy-N-phenyl-1H-imidazo[4,5-b]pyridine-7-carboximidamide;
    • N-(3-ethylphenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide;
    • N-[4-fluoro-3-(trifluoromethoxy)phenyl]-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide;
    • N-(4-fluoro-3-methoxyphenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide;
    • N-(5-bromo-2-fluorophenyl)-N'-hydroxy-3H-imidazo[4,5-b]pyridine-7-carboximidamide;
    • N-(3-bromo-5-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide;
    • N'-hydroxy-N-[3-(trifluoromethyl)phenyl]-1H-imidazo[4,5-b]pyridine-7-carboximidamide;
    • N-[3-fluoro-5-(trifluoromethyl)phenyl]-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide;
    • N-(3-bromophenyl)-N'-hydroxy-3H-imidazo[4,5-b]pyridine-7-carboximidamide;
    • N-(3-bromo-4-fluorophenyl)-N'-hydroxy-3H-imidazo[4,5-b]pyridine-7-carboximidamide;
    • N-(3-chlorophenyl)-N'-hydroxy-3H-imidazo[4,5-b]pyridine-7-carboximidamide;
    • N-[4-fluoro-3-(trifluoromethyl)phenyl]-N'-hydroxy-3H-imidazo[4,5-b]pyridine-7-carboximidamide;
    • N-(4-fluoro-3-prop-1-ynylphenyl)-N'-hydroxy-3H-imidazo[4,5-b]pyridine-7-carboximidamide;
    • N-(3-bromo-4-chlorophenyl)-N'-hydroxy-3H-imidazo[4,5-b]pyridine-7-carboximidamide;
    • N-(3,4-dichlorophenyl)-N'-hydroxy-3H-imidazo[4,5-b]pyridine-7-carboximidamide;
    • N-(4-chlorophenyl)-N'-hydroxy-3H-imidazo[4,5-b]pyridine-7-carboximidamide;
    • N-(4-bromophenyl)-N'-hydroxy-3H-imidazo[4,5-b]pyridine-7-carboximidamide;
    • N-(4-fluorophenyl)-N'-hydroxy-3H-imidazo[4,5-b]pyridine-7-carboximidamide;
    • N-(3-cyano-4-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide;
    • N'-hydroxy-N-[4-(trifluoromethyl)phenyl]-3H-imidazo[4,5-b]pyridine-7-carboximidamide;
    • N'-hydroxy-N-(3-methoxyphenyl)-3H-imidazo[4,5-b]pyridine-7-carboximidamide;
    • N-(4-fluoro-3-propan-2-ylphenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide;
    • N'-hydroxy-N-(4-methylphenyl)-3H-imidazo[4,5-b]pyridine-7-carboximidamide;
    • N-(3-chloro-4-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide;
    • N-(5-chloro-2-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide;
    • N-(5-bromo-2,4-difluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide;
    • N-(5-chloro-2,4-difluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide;
    • N-(2,5-dichlorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide;
    • N-(3,5-dichloro-4-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide;
    • N-(3-chlor2,4-difluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide;
    • N-(3-cyclopropyl-4-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide;
    • N-(4-fluoro-3-phenylphenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide;
    • N-(3-but-1-ynyl-4-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide;
    • N-[3-(2-cyclopropylethynyl)-4-fluorophenyl]-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide; and
    • N'-hydroxy-N-[4-(trifluoromethoxy)phenyl]-1H-imidazo[4,5-b]pyridine-7-carboximidamide.
  • In some embodiments, L is -NR3.
  • In some embodiments, Rt is C1-6 optionally substituted with one, two, or three substituents independently selected from hydroxyl, halo, -NO2, C1-6 haloalkyl, C1-6 haloalkoxy, -N(R20)(R22), -SO2R20, C3-6 cycloalkyl, -CN, and C1-6 alkoxy.
  • In some embodiments,, the compound is selected from the group consisting of:
    • N-(3-chloro-4-fluorophenyl)-2-[2-(dimethylamino)ethyl]-N'-hydroxy-3H-imidazo[4,5-b]pyridine-7-carboximidamide;
    • N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-[2-(methylamino)ethyl]-3H-imidazo[4,5-b]pyridine-7-carboximidamide;
    • N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(2-((2-methoxyethyl)amino)ethyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
    • N-(3-chloro-4-fluorophenyl)-2-[(2,2-dimethylpropylamino)methyl]-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide;
    • N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-[2-(2-methoxyethylamino)ethyl]-3H-imidazo[4,5-b]pyridine-7-carboximidamide;
    • ethyl N-[7-[(Z)-N-(3-chloro-4-fluorophenyl)-N'-hydroxycarbamimidoyl]-1H-imidazo[4,5-b]pyridin-2-yl]carbamate;
    • N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(methylamino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide;
    • N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(2,2,2-trifluoroethylamino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide;
    • N-(3-chloro-4-fluorophenyl)-2-(dimethylamino)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide;
    • N-(3-chloro-4-fluorophenyl)-2-[2-(diethylamino)ethyl]-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide;
    • N-(3-chloro-4-fluorophenyl)-2-[2-(dimethylamino)-1-hydroxyethyl]-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide;
    • N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-[(2-methylpropylamino)methyl]-1H-imidazo[4,5-b]pyridine-7-carboximidamide;
    • N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(methylaminomethyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide;
    • N-(3-chloro-4-fluorophenyl)-2-[2-[2,2-difluoroethyl(methyl)amino]ethyl]-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide;
    • N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(propan-2-ylamino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide;
    • N-(3-chloro-4-fluorophenyl)-2-[(2,2-difluoroethylamino)methyl]-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide;
    • N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-[[(3-hydroxy-2,2-dimethylpropyl)amino]methyl]-1H-imidazo[4,5-b]pyridine-7-carboximidamide;
    • N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-[(propan-2-ylamino)methyl]-3H-imidazo[4,5-b]pyridine-7-carboximidamide;
    • N-(3-chloro-4-fluorophenyl)-2-(ethylaminomethyl)-N'-hydroxy-3H-imidazo[4,5-b]pyridine-7-carboximidamide;
    • N-(3-chloro-4-fluorophenyl)-2-(ethylamino)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide;
    • N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-[(3-methoxypropylamino)methyl]-3H-imidazo[4,5-b]pyridine-7-carboximidamide;
    • N-(3-chloro-4-fluorophenyl)-2-[(dimethylamino)methyl]-N'-hydroxy-3H-imidazo[4,5-b]pyridine-7-carboximidamide;
    • N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-[[3-methoxypropyl(methyl)amino]methyl]-1H-imidazo[4,5-b]pyridine-7-carboximidamide;
    • N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-[(2-methoxyethylamino)methyl]-3H-imidazo[4,5-b]pyridine-7-carboximidamide;
    • N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-[(2,2,2-trifluoroethylamino)methyl]-3H-imidazo[4,5-b]pyridine-7-carboximidamide;
    • N-(3-chloro-4-fluorophenyl)-2-[[2-(dimethylamino)ethylamino]methyl]-N'-hydroxy-3H-imidazo[4,5-b]pyridine-7-carboximidamide;
    • N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-[(3-hydroxypropylamino)methyl]-1H-imidazo[4,5-b]pyridine-7-carboximidamide;
    • N-[[7-[(Z)-N-(3-chloro-4-fluorophenyl)-N'-hydroxycarbamimidoyl]-3H-imidazo[4,5-b]pyridin-2-yl]methyl] acetamide;
    • N-(3-chlorophenyl)-N'-hydroxy-2-(methylamino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide;
    • N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-[2-[2-methoxyethyl(methyl)amino]ethyl]-1H-imidazo[4,5-b]pyridine-7-carboximidamide;
    • N-(3-chloro-4-fluorophenyl)-2-[2-(diethylamino)ethylamino]-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide; and
    • N-(3-chlorophenyl)-2-((dimethylamino)methyl)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide.
  • In some embodiments, L is -NR3 and Rt is C3-15 cycloalkyl, aryl, heteroaryl, or heterocyclyl, wherein said cycloalkyl, aryl, heterocyclyl, or heteroaryl is optionally substituted with one, two, or three substituents independently selected from hydroxyl, halo, -NO2, C1-6 haloalkyl, C1-6 haloalkoxy, C3-6 cycloalkyl, -CN, and C1-6 alkoxy.
  • In some embodiments, the compound is selected from the group consisting of:
    • N-(3-chloro-4-fluorophenyl)-2-(cyclopropylamino)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide;
    • N-(3-chloro-4-fluorophenyl)-2-(cyclopropylmethylamino)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide;
    • N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(2-phenylethylamino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide;
    • 2-anilino-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide;
    • N-(3-chloro-4-fluorophenyl)-2-[(3,3-difluorocyclobutyl)amino]-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide;
    • N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-[(pyrimidin-2-ylamino)methyl]-3H-imidazo[4,5-b]pyridine-7-carboximidamide;
    • N-(3-chloro-4-fluorophenyl)-2-(cyclobutylamino)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide;
    • N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-[(1,3-thiazol-2-ylmethylamino)methyl]-1H-imidazo[4,5-b]pyridine-7-carboximidamide;
    • N-(3-chloro-4-fluorophenyl)-2-[(cyclopropylmethylamino)methyl]-N'-hydroxy-3H-imidazo[4,5-b]pyridine-7-carboximidamide;
    • N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-[(pyridin-2-ylmethylamino)methyl]-3H-imidazo[4,5-b]pyridine-7-carboximidamide;
    • 2-[(benzylamino)methyl]-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-3H-imidazo[4,5-b]pyridine-7-carboximidamide;
    • N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-[[(2-methoxyphenyl)methylamino]methyl]-1H-imidazo[4,5-b]pyridine-7-carboximidamide;
    • N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-[(2-pyridin-2-ylethylamino)methyl]-3H-imidazo[4,5-b]pyridine-7-carboximidamide;
    • N-(3-chloro-4-fluorophenyl)-2-[(cyclopropylamino)methyl]-N'-hydroxy-3H-imidazo[4,5-b]pyridine-7-carboximidamide;
    • N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-[(pyridin-3-ylmethylamino)methyl]-3H-imidazo[4,5-b]pyridine-7-carboximidamide;
    • N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-[(oxan-2-ylmethylamino)methyl]-1H-imidazo[4,5-b]pyridine-7-carboximidamide;
    • 2-(anilinomethyl)-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-3H-imidazo[4,5-b]pyridine-7-carboximidamide;
    • N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-[(oxan-3-ylmethylamino)methyl]-1H-imidazo[4,5-b]pyridine-7-carboximidamide;
    • N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-[(pyrimidin-2-ylmethylamino)methyl]-3H-imidazo[4,5-b]pyridine-7-carboximidamide;
    • N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-[(3-morpholin-4-ylpropylamino)methyl]-3H-imidazo[4,5-b]pyridine-7-carboximidamide;
    • N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-[(oxan-4-ylamino)methyl]-1H-imidazo[4,5-b]pyridine-7-carboximidamide;
    • N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-[(pyridin-4-ylmethylamino)methyl]-3H-imidazo[4,5-b]pyridine-7-carboximidamide;
    • N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-[(pyrazin-2-ylmethylamino)methyl]-1H-imidazo[4,5-b]pyridine-7-carboximidamide;
    • N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-[(oxolan-3-ylmethylamino)methyl]-1H-imidazo[4,5-b]pyridine-7-carboximidamide;
    • N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-[(2-pyrimidin-2-ylethylamino)methyl]-3H-imidazo[4,5-b]pyridine-7-carboximidamide;
    • N-(3-chloro-4-fluorophenyl)-2-[2-[cyclopropylmethyl(methyl)amino]ethyl]-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide;
    • N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(2-morpholin-4-ylethylamino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide;
    • N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-[(1-methylpiperidin-2-yl)methylamino]-1H-imidazo[4,5-b]pyridine-7-carboximidamide; and
    • N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-[(1-methylpyrrolidin-3-yl)amino]-1H-imidazo[4,5-b]pyridine-7-carboximidamide.
  • In some embodiments, L is -NR3 and Rt is hydrogen.
  • In some embodiments, the compound is selected from the group consisting of:
    • 2-(2-aminoethyl)-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-3H-imidazo[4,5-b]pyridine-7-carboximidamide; and
    • 2-amino-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide.
  • In some embodiments, L is -SO2NR3-.
  • In some embodiments, the compound is selected from the group consisting of:
    • 2-(benzenesulfonamidomethyl)-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide, and
    • N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(methanesulfonamidomethyl)-3H-imidazo[4,5-b]pyridine-7-carboximidamide.
  • In some embodiments, X is -N-.
  • In some embodiments, X is -CR2c-.
  • In some embodiments, the compound is selected from the group consisting of:
    • N-(3-chloro-4-fluorophenyl)-6-fluoro-N'-hydroxy-1H-benzimidazole-4-carboximidamide;
    • N-(3-chloro-4-fluorophenyl)-7-fluoro-N'-hydroxy-3H-benzimidazole-4-carboximidamide;
    • 7-chloro-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-3H-benzimidazole-4-carboximidamide;
    • N-(3-chloro-4-fluorophenyl)-N'-hydroxy-7-(trifluoromethyl)-1H-benzimidazole-4-carboximidamide;
    • N-(3-chloro-4-fluorophenyl)-6,7-difluoro-N'-hydroxy-2-(2-morpholin-4-ylethylamino)-3H-benzimidazole-4-carboximidamide;
    • N-(3-chloro-4-fluorophenyl)-6,7-difluoro-N'-hydroxy-2-(methylaminomethyl)-1H-benzimidazole-4-carboximidamide;
    • N-(3-chloro-4-fluorophenyl)-6-fluoro-N'-hydroxy-7-methyl-3H-benzimidazole-4-carboximidamide;
    • N-(3-chloro-4-fluorophenyl)-N'-hydroxy-7-methyl-3H-benzimidazole-4-carboximidamide;
    • N-(3-chloro-4-fluorophenyl)-6,7-difluoro-N'-hydroxy-3H-benzimidazole-4-carboximidamide;
    • N-(3-chloro-4-fluorophenyl)-N'-hydroxy-7-(trifluoromethoxy)-3H-benzimidazole-4-carboximidamide;
    • N-(3-chloro-4-fluorophenyl)-5-fluoro-N'-hydroxy-3H-benzimidazole-4-carboximidamide;
    • N-(3-chloro-4-fluorophenyl)-6,7-difluoro-N'-hydroxy-2-(hydroxymethyl)-3H-benzimidazole-4-carboximidamide;
    • N-(3-chloro-4-fluorophenyl)-6,7-difluoro-N'-hydroxy-2-morpholin-4-yl-3H-benzimidazole-4-carboximidamide;
    • N-(3-chlorophenyl)-6,7-difluoro-N'-hydroxy-2-(1-methylpiperidin-3-yl)-3H-benzimidazole-4-carboximidamide;
    • N-(3-chloro-4-fluorophenyl)-N'-hydroxy-3H-benzimidazole-4-carboximidamide;
    • 6-chloro-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-3H-benzimidazole-4-carboximidamide;
    • 7-bromo-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-3H-benzimidazole-4-carboximidamide;
    • N-(3-chloro-4-fluorophenyl)-6,7-difluoro-N'-hydroxy-2-[(3-methoxypropylamino)methyl]-1H-benzimidazole-4-carboximidamide;
    • N-(3-chloro-4-fluorophenyl)-2-[3-(dimethylamino)propyl]-6,7-difluoro-N'-hydroxy-3H-benzimidazole-4-carboximidamide;
    • N-(3-chloro-4-fluorophenyl)-2-[2-(dimethylamino)ethyl]-6,7-difluoro-N'-hydroxy-1H-benzimidazole-4-carboximidamide;
    • N-(3-chloro-4-fluorophenyl)-6,7-difluoro-N'-hydroxy-2-(methylamino)-3H-benzimidazole-4-carboximidamide;
    • N-(3-bromo-4-fluorophenyl)-2-[2-(dimethylamino)ethyl]-6,7-difluoro-N'-hydroxy-1H-benzimidazole-4-carboximidamide;
    • N-(3-bromophenyl)-2-[2-(dimethylamino)ethyl]-6,7-difluoro-N'-hydroxy-1H-benzimidazole-4-carboximidamide;
    • N-(3-chlorophenyl)-2-[2-(dimethylamino)ethyl]-6,7-difluoro-N'-hydroxy-1H-benzimidazole-4-carboximidamide;
    • N-(3-chloro-4-fluorophenyl)-2-[3-(dimethylamino)propylamino]-6,7-difluoro-N'-hydroxy-3H-benzimidazole-4-carboximidamide;
    • N-(3-chloro-4-fluorophenyl)-6,7-difluoro-N'-hydroxy-2-(2-methoxyethylamino)-3H-benzimidazole-4-carboximidamide;
    • N-(3-chloro-4-fluorophenyl)-2-[2-(dimethylamino)ethylamino]-6,7-difluoro-N'-hydroxy-3H-benzimidazole-4-carboximidamide;
    • N-(3-chloro-4-fluorophenyl)-2-[2-(diethylamino)ethylamino]-6,7-difluoro-N'-hydroxy-3H-benzimidazole-4-carboximidamide;
    • N-(3-chloro-4-fluorophenyl)-6,7-difluoro-N'-hydroxy-2-[(propan-2-ylamino)methyl]-1H-benzimidazole-4-carboximidamide;
    • N-(3-chloro-4-fluorophenyl)-2-[(dimethylamino)methyl]-6,7-difluoro-N'-hydroxy-1H-benzimidazole-4-carboximidamide;
    • N-(3-chloro-4-fluorophenyl)-2-(ethylaminomethyl)-6,7-difluoro-N'-hydroxy-1H-benzimidazole-4-carboximidamide;
    • N-(3-chloro-4-fluorophenyl)-2-[2-(dimethylamino)ethylamino]-7-fluoro-N'-hydroxy-3H-benzimidazole-4-carboximidamide;
    • N-(3-chloro-4-fluorophenyl)-6,7-difluoro-N'-hydroxy-2-[2-(methylamino)ethyl]-1H-benzimidazole-4-carboximidamide;
    • N-(3-chloro-4-fluorophenyl)-2-[2-(diethylamino)ethyl]-6,7-difluoro-N'-hydroxy-1H-benzimidazole-4-carboximidamide;
    • N-(3-chloro-4-fluorophenyl)-7-fluoro-N'-hydroxy-2-(2-methylsulfonylethylamino)-3H-benzimidazole-4-carboximidamide;
    • N-(3-chloro-4-fluorophenyl)-6,7-difluoro-N'-hydroxy-2-(2-methylsulfonylethylamino)-3H-benzimidazole-4-carboximidamide;
    • N-(3-chloro-4-fluorophenyl)-2-[(cyclopropylmethylamino)methyl]-6,7-difluoro-N'-hydroxy-1H-benzimidazole-4-carboximidamide;
    • N-(3-chloro-4-fluorophenyl)-7-fluoro-N'-hydroxy-2-(3-morpholin-4-ylpropylamino)-3H-benzimidazole-4-carboximidamide;
    • N-(3-chloro-4-fluorophenyl)-6,7-difluoro-N'-hydroxy-2-(2-pyrrolidin-1-ylethylamino)-3H-benzimidazole-4-carboximidamide;
    • N-(3-chloro-4-fluorophenyl)-2-[2-(4,4-difluoropiperidin-1-yl)ethylamino]-6,7-difluoro-N'-hydroxy-3H-benzimidazole-4-carboximidamide;
    • N-(3-chloro-4-fluorophenyl)-6,7-difluoro-N'-hydroxy-2-(1-morpholin-4-ylpropan-2-ylamino)-3H-benzimidazole-4-carboximidamide;
    • 2-(aminomethyl)-N-(3-chloro-4-fluorophenyl)-6,7-difluoro-N'-hydroxy-1H-benzimidazole-4-carboximidamide;
    • 2-amino-N-(3-chloro-4-fluorophenyl)-7-fluoro-N'-hydroxy-3H-benzimidazole-4-carboximidamide;
    • 2-amino-N-(3-bromo-4-fluorophenyl)-6,7-difluoro-N'-hydroxy-3H-benzimidazole-4-carboximidamide;
    • 2-amino-N-(3-bromophenyl)-6,7-difluoro-N'-hydroxy-3H-benzimidazole-4-carboximidamide;
    • 2-amino-N-(3-chlorophenyl)-6,7-difluoro-N'-hydroxy-3H-benzimidazole-4-carboximidamide;
    • 2-amino-N-(3-chloro-4-fluorophenyl)-6,7-difluoro-N'-hydroxy-3H-benzimidazole-4-carboximidamide;
    • 2-amino-N-(3-bromophenyl)-7-fluoro-N'-hydroxy-3H-benzimidazole-4-carboximidamide;
    • 2-amino-N-(3-bromo-4-fluorophenyl)-7-fluoro-N'-hydroxy-3H-benzimidazole-4-carboximidamide;
    • 2-amino-N-(3-chlorophenyl)-7-fluoro-N'-hydroxy-3H-benzimidazole-4-carboximidamide;
    • 2-amino-6,7-difluoro-N-[4-fluoro-3-(trifluoromethyl)phenyl]-N'-hydroxy-3H-benzimidazole-4-carboximidamide;
    • 2-amino-7-fluoro-N-[4-fluoro-3-(trifluoromethyl)phenyl]-N'-hydroxy-3H-benzimidazole-4-carboximidamide;
    • N-(3-chlorophenyl)-4,5-difluoro-N'-hydroxy-2-(((3-methoxypropyl)amino)methyl)-1H-benzo[d]imidazole-7-carboximidamide;
    • N-(3-chlorophenyl)-2-(((cyclopropylmethyl)amino)methyl)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide;
    • N-(3-chlorophenyl)-2-((dimethylamino)methyl)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide;
    • N-(3-chlorophenyl)-4,5-difluoro-N'-hydroxy-2-((isopropylamino)methyl)-1H-benzo[d]imidazole-7-carboximidamide;
    • N-(3-chlorophenyl)-2-((ethylamino)methyl)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide;
    • N-(3-chlorophenyl)-4,5-difluoro-N'-hydroxy-2-(hydroxymethyl)-1H-benzo[d]imidazole-7-carboximidamide;
    • N-(3-chlorophenyl)-4,5-difluoro-N'-hydroxy-2-((methylamino)methyl)-1H-benzo[d]imidazole-7-carboximidamide;
    • 2-(aminomethyl)-N-(3-chlorophenyl)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide; and
    • N-(3-chloro-4-fluorophenyl)-4-fluoro-N'-hydroxy-2-((2-morpholinoethyl)amino)-1H-benzo[d]imidazole-7-carboximidamide.
  • In some embodiments, L is -C(O)-NR3-.
  • In some embodiments, the compound is selected from the group consisting of:
    • ethyl N-[7-[(Z)-N-(3-chloro-4-fluorophenyl)-N'-hydroxycarbamimidoyl]-1H-imidazo[4,5-b]pyridin-2-yl]carbamate;
    • N-[[7-[(Z)-N-(3-chloro-4-fluorophenyl)-N'-hydroxycarbamimidoyl]-3H-imidazo[4,5-b]pyridin-2-yl]methyl]acetamide; and
    • propan-2-yl N-[7-[(Z)-N-(3-chloro-4-fluorophenyl)-N'-hydroxycarbamimidoyl]-1H-imidazo[4,5-b]pyridin-2-yl]carbamate.
  • In some embodiments, L is N, m is 1, and n is 0.
  • In some embodiments, L is N, m is 2, and n is 0.
  • In some embodiments, L is N, m is 3, and n is 0.
  • In one embodiment, the compound of Formula I is represented by Formula IA or IB:
    Figure imgb0003
  • In one embodiment, R1 is selected from the group consiting of
    Figure imgb0004
    Figure imgb0005
    Figure imgb0006
    Figure imgb0007
    Figure imgb0008
    Figure imgb0009
    Figure imgb0010
    Figure imgb0011
    Figure imgb0012
    Figure imgb0013
    Figure imgb0014
     and
    Figure imgb0015
  • In one embodiment, R1 is
    Figure imgb0016
  • In one embodiment, the compound of Formula I is represented by Formula II:
    Figure imgb0017
  • In one embodiment, the compound of Formula I is represented by Formula IIA or IIB:
    Figure imgb0018
  • In one embodiment, the compound of Formula I is represented by Formula III:
    Figure imgb0019
  • In one embodiment, the compound of Formula I is represented by Formula IV:
    Figure imgb0020
  • In one embodiment, the group
    Figure imgb0021
     of any Formula described herein is selected from the group consisting of hydrogen, (1-methylpiperidin-2-yl)methylamino, (1-methylpyrrolidin-3-yl)amino, (2-pyrimidin-2-ylethylamino)methyl, (2S)-pyrrolidin-2-yl, (isopropyloxycarbonyl)amino, (1,3-thiazol-2-ylmethylamino)methyl, 1H-imidazol-2-yl, 1H-pyrazol-5-yl, 1H-pyrrol-2-yl, 1-hydroxyethyl, 2-(2-methoxyethylamino)ethyl, 2-(diethylamino)ethyl, 2-(diethylamino)ethylamino, 2-(dimethylamino)-1-hydroxyethyl, 2-(dimethylamino)ethyl, 2-(dimethylamino)ethylamino, [2-(dimethylamino)ethylamino]methyl, 2-(methylamino)ethyl, 2,2,2-trifluoro-1-hydroxyethyl, 2,2,2-trifluoroethylamino, (2,2,2-trifluoroethylamino)methyl, 2-[2,2-difluoroethyl(methyl)amino]ethyl, (2,2-difluoroethylamino)methyl, (2,2-dimethylpropylamino)methyl, 2-[2-methoxyethyl(methyl)amino]ethyl, 2-[cyclopropylmethyl(methyl)amino]ethyl, 2-aminoethyl, 2-hydroxyethyl, 2-hydroxypropan-2-yl, (2-methoxyethylamino)methyl, [(2-methoxyphenyl)methylamino]methyl, 2-morpholin-4-ylethyl, 2-morpholin-4-ylethylamino, 2-phenylethylamino, 2-piperidin-1-ylethyl, (2-pyridin-2-ylethylamino)methyl, 2-pyrrolidin-1-ylethyl, 3-(dimethylamino)propyl, (3,3-difluorocyclobutyl)amino, [(3-hydroxy-2,2-dimethylpropyl)amino]methyl, (3-hydroxypropylamino)methyl, [3-methoxypropyl(methyl)amino]methyl, (3-methoxypropylamino)methyl, 3-morpholin-4-ylpropylamino, (3-morpholin-4-ylpropylamino)methyl, 5-methyl-1H-imidazol-2-yl, 2-methylsulfonylethylamino, 2-(4,4-difluoropiperidin-1-yl)ethylamino, 1-morpholin-4-ylpropan-2-ylamino, 3-(dimethylamino)propylamino, 2-methoxyethylamino, 2-pyrrolidin-1-ylethylamino, 1-methylpiperidin-3-yl, aminomethyl, (dimethylamino)methyl,acetamidomethyl, amino, aminomethyl, anilino, anilinomethyl, benzenesulfonamidomethyl, (benzylamino)methyl, chloromethyl, cyclobutylamino, cyclopropyl, cyclopropyl(hydroxy)methyl, cyclopropylamino, (cyclopropylamino)methyl, cyclopropylmethylamino, (cyclopropylmethylamino)methyl, dimethylamino, ethoxy carbonyl amino, ethyl, ethylamino, ethylaminomethyl, hydroxy(phenyl)methyl, hydroxymethyl, methanesulfonamidomethyl, methoxymethyl, methyl, methylamino, methylaminomethyl, (methylpropylamino)methyl, morpholin-4-yl, morpholin-4-ylmethyl, (oxan-2-ylmethylamino)methyl, (oxan-3-ylmethylamino)methyl, (oxan-4-ylamino)methyl, (oxolan-3-ylmethylamino)methyl, piperidin-1-ylmethyl, propan-2-ylamino, (propan-2-ylamino)methyl, (pyrazin-2-ylmethylamino)methyl, pyridin-3-yl, (pyridin-3-ylmethylamino)methyl, (pyridin-4-ylmethylamino)methyl, (pyrimidin-2-ylamino)methyl, (pyrimidin-2-ylmethylamino)methyl, pyrrolidin-1-ylmethyl, and thiophen-2-yl.
  • In one embodiment, the group
    Figure imgb0022
     of any Formula described herein is selected from the group consisting of:
    -H,
    Figure imgb0023
    Figure imgb0024
    Figure imgb0025
    Figure imgb0026
    Figure imgb0027
    Figure imgb0028
    Figure imgb0029
    Figure imgb0030
    Figure imgb0031
    Figure imgb0032
    Figure imgb0033
    Figure imgb0034
    Figure imgb0035
    Figure imgb0036
    Figure imgb0037
    Figure imgb0038
    Figure imgb0039
    Figure imgb0040
    Figure imgb0041
    Figure imgb0042
    Figure imgb0043
    Figure imgb0044
    Figure imgb0045
    Figure imgb0046
    Figure imgb0047
    Figure imgb0048
    Figure imgb0049
    Figure imgb0050
    Figure imgb0051
    Figure imgb0052
    Figure imgb0053
    Figure imgb0054
    Figure imgb0055
    Figure imgb0056
    Figure imgb0057
    Figure imgb0058
    Figure imgb0059
    Figure imgb0060
    Figure imgb0061
    Figure imgb0062
    Figure imgb0063
    Figure imgb0064
    Figure imgb0065
    Figure imgb0066
    Figure imgb0067
    Figure imgb0068
    Figure imgb0069
    Figure imgb0070
    Figure imgb0071
    Figure imgb0072
    Figure imgb0073
    Figure imgb0074
    Figure imgb0075
    Figure imgb0076
    Figure imgb0077
    Figure imgb0078
    Figure imgb0079
    Figure imgb0080
    Figure imgb0081
    Figure imgb0082
    Figure imgb0083
    Figure imgb0084
    Figure imgb0085
    Figure imgb0086
    Figure imgb0087
    Figure imgb0088
    Figure imgb0089
    Figure imgb0090
    Figure imgb0091
  • In one embodiment, the group
    Figure imgb0092
     of any Formula described herein is selected from the group consisting of:
    -H,
    Figure imgb0093
    Figure imgb0094
    Figure imgb0095
    Figure imgb0096
    Figure imgb0097
    Figure imgb0098
    Figure imgb0099
    Figure imgb0100
    Figure imgb0101
    Figure imgb0102
    Figure imgb0103
    Figure imgb0104
    Figure imgb0105
     -NH2,
    Figure imgb0106
    Figure imgb0107
    Figure imgb0108
    Figure imgb0109
    Figure imgb0110
    Figure imgb0111
    Figure imgb0112
    Figure imgb0113
  • In one embodiment, the group
    Figure imgb0114
     of any Formula described herein is selected from the group consisting of:
    Figure imgb0115
    Figure imgb0116
    Figure imgb0117
    Figure imgb0118
    Figure imgb0119
    Figure imgb0120
    Figure imgb0121
    Figure imgb0122
    Figure imgb0123
    Figure imgb0124
    Figure imgb0125
    Figure imgb0126
    Figure imgb0127
     -NH2,
    Figure imgb0128
    Figure imgb0129
    Figure imgb0130
    Figure imgb0131
    Figure imgb0132
    Figure imgb0133
    Figure imgb0134
  • In one embodiment, the compound of Formula I is represented by Formula IIA or IIB:
    Figure imgb0135
    • wherein R2a, R2b, X, Rm, Rn, m, n, and Rt are as defined herein and each R1a is independently hydroxyl, halo, -CN, C1-6 haloalkoxy, C1-6 haloalkyl, C1-6 alkoxy, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C3-6 cycloalkyl, or two of the optional substituents can join to form an additional partially saturated heterocyclic ring, and
    • s is 0, 1, 2 or 3.
  • In some embodiments, each R1a is independently hydroxyl, halo, -CN, C1-6 haloalkoxy, or C1-6 haloalkyl. In some embodiments, each R1a is independently halo or - CF3. In some embodiments, each R1a is independently halo. In some embodiments, s is 0. In some embodiments, s is 1. In some embodiments, s is 2. In some embodiments, s is 3.
  • In general, the specific compounds exemplified herein are named using ChemBioDraw Ultra. However, it is understood that other names may be used to identify compounds of the same structure. In particular, the compounds may also be named using other nomenclature systems and symbols that are commonly recognized in the art of chemistry including, for example, Chemical Abstract Service (CAS) and International Union of Pure and Applied Chemistry (IUPAC). Other compounds or radicals may be named with common names, or systematic or non-systematic names.
  • For example, the compound of Example 10 (shown below) may be referred to as N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide or N-(3-chloro-4-fluorophenyl)-6,7-difluoro-N'-hydroxy-3H-benzimidazole-4-carboximidamide, where both names provide the structure below.
    Figure imgb0136
  • Provided are also all tautomeric forms of the compounds of any Formula described herein. Tautomeric isomers are in equilibrium with one another. Regardless of which tautomer is shown, and regardless of the nature of the equilibrium among tautomers, the compounds are understood by one of ordinary skill in the art to comprise both. Non-limiting examples of benzimidazole and imidazo[4,5-b]pyridine tautomers are shown below:
    Figure imgb0137
  • Provided are also compounds described herein or pharmaceutically acceptable salts, or a mixture thereof, in which from 1 to n hydrogen atoms attached to a carbon atom may be replaced by a deuterium atom or D, in which n is the number of hydrogen atoms in the molecule. As known in the art, the deuterium atom is a non-radioactive isotope of the hydrogen atom. Such compounds may increase resistance to metabolism, and thus may be useful for increasing the half-life of the compounds described herein or pharmaceutically acceptable salts, isomer, or a mixture thereof when administered to a mammal. See, e.g., Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism", Trends Pharmacol. Sci., 5(12):524-527 (1984). Such compounds are synthesized by means well known in the art, for example by employing starting materials in which one or more hydrogen atoms have been replaced by deuterium.
  • Provided are also pharmaceutically acceptable salts, hydrates, solvates, tautomeric forms, polymorphs, and prodrugs of the compounds described herein. "Pharmaceutically acceptable" or "physiologically acceptable" refer to compounds, salts, compositions, dosage forms and other materials which are useful in preparing a pharmaceutical composition that is suitable for veterinary or human pharmaceutical use. "Pharmaceutically acceptable salts" or "physiologically acceptable salts" include, for example, salts with inorganic acids and salts with an organic acid. In addition, if the compounds described herein are obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds. Those skilled in the art will recognize various synthetic methodologies that may be used to prepare nontoxic pharmaceutically acceptable addition salts.
  • A "solvate" is formed by the interaction of a solvent and a compound. Solvates of salts of the compounds described herein are also provided. Hydrates of the compounds described herein are also provided.
  • A "prodrug" is a biologically inactive derivative of a drug that upon administration to the human body is converted to the biologically active parent drug according to some chemical or enzymatic pathway.
  • In certain embodiments, provided are optical isomers, racemates, or other mixtures thereof of the compounds described herein or pharmaceutically acceptable salts or a mixture thereof. In those situations, the single enantiomer or diastereomer, i.e., optically active form, can be obtained by asymmetric synthesis or by resolution of the racemate. Resolution of racemates can be accomplished, for example, by conventional methods such as crystallization in the presence of a resolving agent, or chromatography, using, for example a chiral high pressure liquid chromatography (HPLC) column. In addition, provided are also Z- and E- forms (or cis- and trans- forms) of the hydroxyamidine compounds described herein. Specifically, Z- and E- forms are included even if only one designation is named for both carbon-carbon double bonds as well as the hydroxyamidine bond.
  • Compositions provided herein that include a compound described herein or pharmaceutically acceptable salts, or a mixture thereof may include racemic mixtures, or mixtures containing an enantiomeric excess of one enantiomer or single diastereomers or diastereomeric mixtures. All such isomeric forms of these compounds are expressly included herein the same as if each and every isomeric form were specifically and individually listed.
  • In certain embodiments, provided herein are also crystalline and amorphous forms of the compounds described herein or pharmaceutically acceptable salts, isomer, or a mixture thereof.
  • In certain embodiments, provided are also chelates, non-covalent complexes, and mixtures thereof, of the compounds described herein or pharmaceutically acceptable salts, or a mixture thereof. A "chelate" is formed by the coordination of a compound to a metal ion at two (or more) points. A "non-covalent complex" is formed by the interaction of a compound and another molecule wherein a covalent bond is not formed between the compound and the molecule. For example, complexation can occur through van der Waals interactions, hydrogen bonding, and electrostatic interactions (also called ionic bonding).
    • Therapeutic Uses of the Compounds
  • The methods described herein may be applied to cell populations in vivo or ex vivo. "In vivo" means within a living individual, as within an animal or human. In this context, the methods described herein may be used therapeutically in an individual. "Ex vivo" means outside of a living individual. Examples of ex vivo cell populations include in vitro cell cultures and biological samples including fluid or tissue samples obtained from individuals. Such samples may be obtained by methods well known in the art. Exemplary biological fluid samples include blood, cerebrospinal fluid, urine, and saliva. Exemplary tissue samples include tumors and biopsies thereof. In this context, the invention may be used for a variety of purposes, including therapeutic and experimental purposes. For example, the invention may be used ex vivo to determine the optimal schedule and/or dosing of administration of an IDOl inhibitor for a given indication, cell type, individual, and other parameters. Information gleaned from such use may be used for experimental purposes or in the clinic to set protocols for in vivo treatment. Other ex vivo uses for which the invention may be suited are described below or will become apparent to those skilled in the art. The selected compounds may be further characterized to examine the safety or tolerance dosage in human or non-human subjects. Such properties may be examined using commonly known methods to those skilled in the art.
  • In some embodiments, the compounds described herein may be used to treat subjects who have or are suspected of having disease states, disorders, and conditions (also collectively referred to as "indications") responsive or believed to be responsive to the inhibition of IDO1 activity. In some embodiments, the compounds described herein may be used to inhibit the activity of an IDOl polypeptide. In some embodiments, the compounds described herein may be used to inhibit excessive or destructive immune reactions or growth or a proliferation of a cell, such as a cancer cell, or inhibit immunosuppression.
  • Example indications suitable for treatment with compounds described here include, without limitation cancer, viral infection such as HIV infection, HBV infection, HCV infection, other infections (e.g., skin infections, GI infection, urinary tract infections, genito-urinary infections, and systemic infections), depression, neurodegenerative disorders such as Alzheimer's disease and Huntington's disease, trauma, age-related cataracts, organ transplantation (e.g., organ transplant rejection), and autoimmune diseases.
  • Examples of autoimmune diseases include, but are not limited to, asthma, collagen diseases such as rheumatoid arthritis, systemic lupus erythematosus. Sharp's syndrome, CREST syndrome (calcinosis, Raynaud's syndrome, esophageal dysmotility, sclerodactyly, telangiectasia), dermatomyositis, vasculitis (Morbus Wegener's) and Sjögren's syndrome, renal diseases such as Goodpasture's syndrome, rapidly- progressing glomerulonephritis and membrano-proliferative glomerulonephritis type II, endocrine diseases such as type-I diabetes, autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), autoimmune parathyroidism, pernicious anemia, gonad insufficiency, idiopathic Morbus Addison's, hyperthyreosis, Hashimoto's thyroiditis and primary myxedema, skin diseases such as pemphigus vulgaris, bullous pemphigoid, herpes gestationis, epidermolysis bullosa and erythema multiforme major, liver diseases such as primary biliary cirrhosis, autoimmune cholangitis, autoimmune hepatitis type-1, autoimmune hepatitis type-2, primary sclerosing cholangitis, neuronal diseases such as multiple sclerosis, myasthenia gravis, myasthenic Lambert-Eaton syndrome, acquired neuromyotomy, Guillain-Barre syndrome (Muller-Fischer syndrome), stiff-man syndrome, cerebellar degeneration, ataxia, opsoclonus, sensoric neuropathy and achalasia, blood diseases such as autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura (Morbus Werlhof), infectious diseases with associated autoimmune reactions such as AIDS, allergic inflammation, inflammatory bowel disease, psoriasis and systemic lupus erythematosusor, malaria and Chagas disease.
  • In some embodiments, the compounds described herein may be used for treating cancer, viral infection, depression, a neurodegenerative disorder, trauma, age-related cataracts, organ transplant rejection, or an autoimmune disease.
  • In other embodiments, the disease to be treated is a solid tumor. In particular embodiments, the solid tumor is from pancreatic cancer, bladder cancer, colorectal cancer, breast cancer, prostate cancer, renal cancer, hepatocellular cancer, lung cancer, ovarian cancer, cervical cancer, gastric cancer, esophageal cancer, head and neck cancer, melanoma, neuroendocrine cancers, CNS cancers, brain tumors (e.g., glioma, anaplastic oligodendroglioma, adult glioblastoma multiforme, and adult anaplastic astrocytoma), bone cancer, or soft tissue sarcoma. In some embodiments, the solid tumor is from non-small cell lung cancer, small-cell lung cancer, colon cancer, CNS cancer, melanoma, ovarian cancer, renal cancer, prostate cancer, or breast cancer..
  • In some embodiments, the disease is an autoimmune disease. In particular embodiments, the autoimmune disease is systemic lupus erythematosus (SLE), myestenia gravis, rheumatoid arthritis (RA), acute disseminated encephalomyelitis, idiopathic thrombocytopenic purpura, multiple sclerosis (MS), psoriasis, Sjoegren's syndrome, psoriasis, autoimmune hemolytic anemia, asthma, or chronic obstructive pulmonary disease (COPD). In other embodiments, the disease is inflammation. In yet other embodiments, the disease is excessive or destructive immune reactions, such as asthma, rheumatoid arthritis, multiple sclerosis, chronic obstructive pulmonary disease (COPD), and lupus.
  • Provided is a compound of formula I for use in a method for treating a subject, who has or is suspected of having a disease or condition responsive or believed to be responsive to the inhibition of IDO1 activity by administering to the subject the compound described herein or pharmaceutically acceptable salts, or a mixture thereof. Provided is also a method of inhibiting kinase activity of a IDO1 polypeptide by contacting the polypeptide with the compound described herein or pharmaceutically acceptable salts, isomer, or a mixture thereof. Provided is also a compound of formula I for use in a method of inhibiting a growth or a proliferation of cancer cells of hematopoietic origin comprising contacting the cancer cells with an effective amount of a compound described herein or pharmaceutically acceptable salts, isomer, or a mixture thereof.
  • In one embodiment, the compounds of the present application may be used in combination with one or more additional therapeutic agent that are being used and/or developed to treat cancers or inflammatory disorders. The one or more additional therapeutic agent may be a chemotherapeutic agent, an immunotherapeutic agent, a radiotherapeutic agent, an anti-neoplastic agent, an anti-cancer agent, an anti-proliferation agent, an anti-fibrotic agent, an anti-angiogenic agent, a therapeutic antibody, or any combination thereof.
  • The one or more additional therapeutic agent may be an inhibitor to PI3K such as PI3Kγ, PI3Kβ, PI3Kδ, and/or PI3Kα, Janus kinase (JAK) such as JAK1, JAK2 and/or JAK3 , spleen tyrosine kinase (SYK), Bruton's tyrosine kinase (BTK), bromodomain containing protein inhibitor (BRD) such as BRD4, a lysyl oxidase protein (LOX), lysyl oxidase-like protein (LOXL) such as LOXL1-5, matrix metalloprotease (MMP) such as MMP 1-10, adenosine A2B receptor (A2B), isocitrate dehydrogenase (IDH) such as IDH1, apoptosis signal-regulating kinase (ASK) such as ASK1, serine/threonine kinase TPL2, discoidin domain receptor (DDR) such as DDR1 and DDR2, histone deacetylase (HDAC), protein kinase C (PKC), or any combination thereof.
  • A phosphoinositide 3-kinase inhibitor (PI3K inhibitor) functions by inhibiting one or more of the phosphoinositide 3-kinase enzymes, including but not limited to PI3Kγ, PI3Kβ, PI3Kδ, and PI3Kα. Non-limiting examples of PI3K inhibitors include wortmannin, demethoxyviridin, LY294002, idelalisib, perifosine, PX-866, IPI-145, BAY 80-6946, BEZ235, RP6530, TGR 1202, INK1117, GDC-0941, BKM120, XL147 (also known as SAR245408), XL765 (also known as SAR245409), Palomid 529, GSK1059615, ZSTK474, PWT33597, IC87114, CAL263, RP6503, PI-103, GNE-477, CUDC-907 and AEZS-136. In some embodiments, the PI3K inhibitor is a PI3Kδ inhibitors, such as idelalisib, IPI-145, RP6530, and RP6503, as well as those disclosed in U.S. Patent No. 8,569,296 , and PCT publications WO 2014/006572 and WO 2015/001491 .
  • In some embodiments, the one or more additional therapeutic agent may be an MMP9 inhibitor, or an agent that inhibits the expression and/or activity of MMP9. A representative protein sequence for MMP9 is GenBank Accession No. NP_004985. The inhibitor can be small molecule or biologic. For instance, Gu et al., The Journal of Neuroscience, 25(27): 6401-6408 (2005) discloses a specific MMP9 inhibitor, SB-3CT (CAS 292605-14-2). Further, siRNA, antisense RNA and antibodies have also been demonstrated to inhibit the expression or activity of MMP9 and are within the scope of the present disclosure. In one embodiment, an MMP9 inhibitor is a monoclonal anti-MMP9 antibody. In some embodiment, the one or more additional therapeutic agent includes an MMP9 inhibitor and a nucleoside analog such as gemcitabine.
  • One, two, three, or more of the therapeutic agents (e.g. a PI3K inhibitor, a JAK inhibitor, a SYK inhibitor, a BTK inhibitor, a BRD4 inhibitor, a LOXL2 inhibitor, a MMP9 inhibitor, a A2B inhibitor, an IDH inhibitor, an ASK inhibitor, a TPL2 inhibitor, a DDR1 inhibitor, a TBK inhibitor, a HDAC inhibitor, a PKC inhibitor) may be further used or combined with a chemotherapeutic agent, an immunotherapeutic agent, a radiotherapeutic agent, an anti-neoplastic agent, an anti-cancer agent, an anti-fibrotic agent, an anti-angiogenic agent, a therapeutic antibody, or any combination thereof.
  • Chemotherapeutic agents may be categorized by their mechanism of action into, for example, the following groups: anti-metabolites/anti-cancer agents, such as pyrimidine analogs (floxuridine, capecitabine, and cytarabine); purine analogs, folate antagonists and related inhibitors, antiproliferative/antimitotic agents including natural products such as vinca alkaloid (vinblastine, vincristine) and microtubule such as taxane (paclitaxel, docetaxel), vinblastin, nocodazole, epothilones and navelbine, epidipodophyllotoxins (etoposide, teniposide); DNA damaging agents (actinomycin, amsacrine, busulfan, carboplatin, chlorambucil, cisplatin, cyclophosphamide, Cytoxan, dactinomycin, daunorubicin, doxorubicin, epirubicin, iphosphamide, melphalan, merchlorehtamine, mitomycin, mitoxantrone, nitrosourea, procarbazine, taxol, taxotere, teniposide, etoposide, triethylenethiophosphoramide); antibiotics such as dactinomycin (actinomycin D), daunorubicin, doxorubicin (adriamycin), idarubicin, anthracyclines, mitoxantrone, bleomycins, plicamycin (mithramycin) and mitomycin; enzymes (L-asparaginase which systemically metabolizes L-asparagine and deprives cells which do not have the capacity to synthesize their own asparagine); antiplatelet agents; antiproliferative/ antimitotic alkylating agents such as nitrogen mustards cyclophosphamide and analogs, melphalan, chlorambucil), and (hexamethylmelamine and thiotepa), alkyl nitrosoureas (BCNU) and analogs, streptozocin), trazenes-dacarbazinine (DTIC); antiproliferative/antimitotic antimetabolites such as folic acid analogs (methotrexate); platinum coordination complexes (cisplatin, oxiloplatinim, carboplatin), procarbazine, hydroxyurea, mitotane, aminoglutethimide; hormones, hormone analogs (estrogen, tamoxifen, goserelin, bicalutamide, nilutamide) and aromatase inhibitors (letrozole, anastrozole); anticoagulants (heparin, synthetic heparin salts and other inhibitors of thrombin); fibrinolytic agents (such as tissue plasminogen activator, streptokinase and urokinase), aspirin, dipyridamole, ticlopidine, clopidogrel; antimigratory agents; antisecretory agents (breveldin); immunosuppressives tacrolimus sirolimus azathioprine, mycophenolate; compounds (TNP-470, genistein) and growth factor inhibitors (vascular endothelial growth factor inhibitors, fibroblast growth factor inhibitors); angiotensin receptor blocker, nitric oxide donors; anti-sense oligonucleotides; antibodies (trastuzumab, rituximab); cell cycle inhibitors and differentiation inducers (tretinoin); inhibitors, topoisomerase inhibitors (doxorubicin (adriamycin), daunorubicin, dactinomycin, eniposide, epirubicin, etoposide, idarubicin, irinotecan and mitoxantrone, topotecan, irinotecan, camptothesin), corticosteroids (cortisone, dexamethasone, hydrocortisone, methylpednisolone, prednisone, and prenisolone); growth factor signal transduction kinase inhibitors; dysfunction inducers, toxins such as Cholera toxin, ricin, Pseudomonas exotoxin, Bordetella pertussis adenylate cyclase toxin, or diphtheria toxin, and caspase activators; and chromatin.
  • As used herein the term "chemotherapeutic agent" or "chemotherapeutic" (or "chemotherapy," in the case of treatment with a chemotherapeutic agent) is meant to encompass any non-proteinaceous (i.e., non-peptidic) chemical compound useful in the treatment of cancer. Examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclophosphamide (CYTOXAN); alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; emylerumines and memylamelamines including alfretamine, triemylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide and trimemylolomelamine; acetogenins (especially bullatacin and bullatacinone); a camptothecin (including synthetic analogue topotecan); bryostatin; callystatin; CC-1065 (including its adozelesin, carzelesin and bizelesin synthetic analogues); cryptophycins (articularly cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycin (including the synthetic analogues, KW-2189 and CBI-TMI); eleutherobin; pancratistatin; a sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil, chlomaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosoureas such as carmustine, chlorozotocin, foremustine, lomustine, nimustine, ranimustine; antibiotics such as the enediyne antibiotics (e.g., calicheamicin, especially calicheamicin gammaII and calicheamicin phiI1, see, e.g., Agnew, Chem. Intl. Ed. Engl, 33:183-186 (1994); dynemicin, including dynemicin A; bisphosphonates, such as clodronate; an esperamicin; as well as neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromomophores), aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, carrninomycin, carzinophilin, chromomycins, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin (including morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogues such as demopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogues such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; anti-adrenals such as aminoglutethimide, mitotane, trilostane; folic acid replinisher such as frolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; hestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elformthine; elliptinium acetate; an epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan; leucovorin; lonidamine; maytansinoids such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidamol; nitracrine; pentostatin; phenamet; pirarubicin; losoxantrone; fluoropyrimidine; folinic acid; podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK(r); razoxane; rhizoxin; sizofiran; spirogermanium; tenuazonic acid; triaziquone; 2,2',2"-tricUorotriemylamine; trichothecenes (especially T-2 toxin, verracurin A, roridin A and anguidine); urethane; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside ("Ara-C"); cyclophosphamide; thiopeta; taxoids, e.g., paclitaxel (TAXOL(r) and docetaxel (TAXOTERE(r)); chlorambucil; gemcitabine (Gemzar(r)); 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin and carboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitroxantrone; vancristine; vinorelbine (Navelbine(r)); novantrone; teniposide; edatrexate; daunomycin; aminopterin; xeoloda; ibandronate; CPT-11; topoisomerase inhibitor RFS 2000; difluoromethylomithine (DMFO); retinoids such as retinoic acid; capecitabine; FOLFIRI (fluorouracil, leucovorin, and irinotecan) and pharmaceutically acceptable salts, acids or derivatives of any of the above. One or more chemotherapeutic agent are used or included in the present application. For example, gemcitabine, nab-paclitaxel, and gemcitabine/nab-paclitaxel are used with the JAK inhibitor and/or PI3Kδ inhibitor for treating hyperproliferative disorders.
  • Also included in the definition of "chemotherapeutic agent" are anti-hormonal agents that act to regulate or inhibit hormone action on tumors such as antiestrogens and selective estrogen receptor modulators (SERMs), including, for example, tamoxifen (including Nolvadex™), raloxifene, droloxifene, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone, and toremifene (Fareston(r)); inhibitors of the enzyme aromatase, which regulates estrogen production in the adrenal glands, such as, for example, 4(5)-imidazoles, aminoglutethimide, megestrol acetate (Megace(r)), exemestane, formestane, fadrozole, vorozole (Rivisor(r)), letrozole (Femara(r)), and anastrozole (Arimidex(r).); and anti-androgens such as flutamide, nilutamide, bicalutamide, leuprohde, and goserelin; and pharmaceutically acceptable salts, acids or derivatives of any of the above.
  • The anti-angiogenic agents include, but are not limited to, retinoid acid and derivatives thereof, 2-methoxyestradiol, ANGIOSTATIN(r), ENDOSTATIN(r), suramin, squalamine, tissue inhibitor of metalloproteinase-1, tissue inhibitor of metalloproternase-2, plasminogen activator inhibitor-1, plasminogen activator inhibitor-2, cartilage-derived inhibitor, paclitaxel (nab-paclitaxel), platelet factor 4, protamine sulphate (clupeine), sulfated chitin derivatives (prepared from queen crab shells), sulfated polysaccharide peptidoglycan complex (sp-pg), staurosporine, modulators of matrix metabolism, including for example, proline analogs ((1-azetidine-2-carboxylic acid (LACA), cishydroxyproline, D,L-3,4-dehydroproline, thiaproline, .alpha.-dipyridyl, beta-aminopropionitrile fumarate, 4-propyl-5-(4-pyridinyl)-2(3H)-oxazolone; methotrexate, mitoxantrone, heparin, interferons, 2 macroglobulin-serum, chimp-3, chymostatin, beta-cyclodextrin tetradecasulfate, eponemycin; fumagillin, gold sodium thiomalate, d-penicillamine (CDPT), beta-1-anticollagenase-serum, alpba-2-antiplasmin, bisantrene, lobenzarit disodium, n-2-carboxyphenyl-4-chloroanthronilic acid disodium or "CCA", thalidomide; angiostatic steroid, cargboxynaminolmidazole; metalloproteinase inhibitors such as BB94. Other anti-angiogenesis agents include antibodies, preferably monoclonal antibodies against these angiogenic growth factors: beta-FGF, alpha-FGF, FGF-5, VEGF isoforms, VEGF-C, HGF/SF and Ang-1/Ang-2. See Ferrara N. and Alitalo, K. "Clinical application of angiogenic growth factors and their inhibitors" (1999) Nature Medicine 5:1359-1364.
  • The anti-fibrotic agents include, but are not limited to, the compounds such as beta-aminoproprionitrile (BAPN), as well as the compounds disclosed in U.S. Pat. No. 4,965,288 to Palfreyman, et al., issued Oct. 23, 1990 , entitled "Inhibitors of lysyl oxidase," relating to inhibitors of lysyl oxidase and their use in the treatment of diseases and conditions associated with the abnormal deposition of collagen; U.S. Pat. No. 4,997,854 to Kagan, et al., issued Mar. 5, 1991 , entitled "Anti-fibrotic agents and methods for inhibiting the activity of lysyl oxidase in situ using adjacently positioned diamine analogue substrate," relating to compounds which inhibit LOX for the treatment of various pathological fibrotic states, which are herein incorporated by reference. Further exemplary inhibitors are described in U.S. Pat. No. 4,943,593 to Palfreyman, et al., issued Jul. 24, 1990 , entitled "Inhibitors of lysyl oxidase," relating to compounds such as 2-isobutyl-3-fluoro-, chloro-, or bromo-allylamine; as well as, e.g., U.S. Pat. No. 5,021,456 ; U.S. Pat. No. 5,5059,714 ; U.S. Pat. No. 5,120,764 ; U.S. Pat. No. 5,182,297 ; U.S. Pat. No. 5,252,608 (relating to 2-(1-naphthyloxymemyl)-3-fluoroallylamine); and U.S. Patent Application No. 2004/0248871 , which are herein incorporated by reference. Exemplary anti-fibrotic agents also include the primary amines reacting with the carbonyl group of the active site of the lysyl oxidases, and more particularly those which produce, after binding with the carbonyl, a product stabilized by resonance, such as the following primary amines: emylenemamine, hydrazine, phenylhydrazine, and their derivatives, semicarbazide, and urea derivatives, aminonitriles, such as beta-aminopropionitrile (BAPN), or 2-nitroethylamine, unsaturated or saturated haloamines, such as 2-bromo-ethylamine, 2-chloroethylamine, 2-trifluoroethylamine, 3-bromopropylamine, p-halobenzylamines, selenohomocysteine lactone. Also, the anti-fibrotic agents are copper chelating agents, penetrating or not penetrating the cells. Exemplary compounds include indirect inhibitors such compounds blocking the aldehyde derivatives originating from the oxidative deamination of the lysyl and hydroxylysyl residues by the lysyl oxidases, such as the thiolamines, in particular D-penicillamine, or its analogues such as 2-amino-5-mercapto-5-methylhexanoic acid, D-2-amino-3-methyl-3-((2-acetamidoethyl)dithio)butanoic acid, p-2-amino-3-methyl-3-((2-aminoethyl)dithio)butanoic acid, sodium-4-((p-1-dimethyl-2-amino-2-carboxyethyl)dithio)butane sulphurate, 2-acetamidoethyl-2-acetamidoethanethiol sulphanate, sodium-4-mercaptobutanesulphinate trihydrate.
  • The immunotherapeutic agents include and are not limited to therapeutic antibodies suitable for treating patients; such as abagovomab, adecatumumab, afutuzumab, alemtuzumab, altumomab, amatuximab, anatumomab, arcitumomab, bavituximab, bectumomab, bevacizumab, bivatuzumab, blinatumomab, brentuximab, cantuzumab, catumaxomab, cetuximab, citatuzumab, cixutumumab, clivatuzumab, conatumumab, daratumumab, drozitumab, duligotumab, dusigitumab, detumomab, dacetuzumab, dalotuzumab, ecromeximab, elotuzumab, ensituximab, ertumaxomab, etaracizumab, farietuzumab, ficlatuzumab, figitumumab, flanvotumab, futuximab, ganitumab, gemtuzumab, girentuximab, glembatumumab, ibritumomab, igovomab, imgatuzumab, indatuximab, inotuzumab, intetumumab, ipilimumab, iratumumab, labetuzumab, lexatumumab, lintuzumab, lorvotuzumab, lucatumumab, mapatumumab, matuzumab, milatuzumab, minretumomab, mitumomab, moxetumomab, narnatumab, naptumomab, necitumumab, , nimotuzumab, nofetumomabn, ocaratuzumab, ofatumumab, olaratumab, onartuzumab, oportuzumab, oregovomab, panitumumab, parsatuzumab, patritumab, pemtumomab, pertuzumab, pintumomab, pritumumab, racotumomab, radretumab, rilotumumab, rituximab, robatumumab, satumomab, sibrotuzumab, siltuximab, simtuzumab, solitomab, tacatuzumab, taplitumomab, tenatumomab, teprotumumab, tigatuzumab, tositumomab, trastuzumab, tucotuzumab, ublituximab, veltuzumab, vorsetuzumab, votumumab, zalutumumab, CC49 and 3F8. The exemplified therapeutic antibodies may be further labeled or combined with a radioisotope particle, such as indium In 111, yttrium Y 90, iodine 1-131.
  • The application also provides a compound of formula I for use in a method for treating a subject who is undergoing one or more standard therapies, such as chemotherapy, radiotherapy, immunotherapy, surgery, or combination thereof. Accordingly, one or more therapeutic agent or inhibitors may be administered before, during, or after administration of chemotherapy, radiotherapy, immunotherapy, surgery or combination thereof.
  • In certain embodiments, the subject may be a human who is (i) substantially refractory to at least one chemotherapy treatment, or (ii) in relapse after treatment with chemotherapy, or both (i) and (ii). In some of embodiments, the subject is refractory to at least two, at least three, or at least four chemotherapy treatments (including standard or experimental chemotherapies).
  • In certain embodiments, the subject is refractory to at least one, at least two, at least three, or at least four chemotherapy treatment (including standard or experimental chemotherapy) selected from fludarabine, rituximab, obinutuzumab, alkylating agents, alemtuzumab and other chemotherapy treatments such as CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone); R-CHOP (rituximab-CHOP); hyperCVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone, methotrexate, cytarabine); R-hyperCVAD (rituximab-hyperCVAD); FCM (fludarabine, cyclophosphamide, mitoxantrone); R-FCM (rituximab, fludarabine, cyclophosphamide, mitoxantrone); bortezomib and rituximab; temsirolimus and rituximab; temsirolimus and Velcade®; Iodine-131 tositumomab (Bexxar®) and CHOP; CVP (cyclophosphamide, vincristine, prednisone); R-CVP (rituximab-CVP); ICE (iphosphamide, carboplatin, etoposide); R-ICE (rituximab-ICE); FCR (fludarabine, cyclophosphamide, rituximab); FR (fludarabine, rituximab); and D.T. PACE (dexamethasone, thalidomide, cisplatin, Adriamycin®, cyclophosphamide, etoposide).
  • Other examples of chemotherapy treatments (including standard or experimental chemotherapies) are described below. In addition, treatment of certain lymphomas is reviewed in Cheson, B.D., Leonard, J.P., "Monoclonal Antibody Therapy for B-Cell Non-Hodgkin's Lymphoma" The New England Journal of Medicine 2008, 359(6), p. 613-626; and Wierda, W.G., "Current and Investigational Therapies for Patients with CLL" Hematology 2006, p. 285-294. Lymphoma incidence patterns in the United States is profiled in Morton, L.M., et al. "Lymphoma Incidence Patterns by WHO Subtype in the United States, 1992-2001" Blood 2006, 107(1), p. 265-276.
  • Examples of immunotherapeutic agents treating lymphoma or leukemia include, but are not limited to, rituximab (such as Rituxan), alemtuzumab (such as Campath, MabCampath), anti-CD 19 antibodies, anti-CD20 antibodies, anti-MN-14 antibodies, anti-TRAIL, Anti-TRAIL DR4 and DR5 antibodies, anti-CD74 antibodies, apolizumab, bevacizumab, CHIR-12.12, epratuzumab (hLL2- anti-CD22 humanized antibody), galiximab, ha20, ibritumomab tiuxetan, lumiliximab, milatuzumab, ofatumumab, PRO131921, SGN-40, WT-1 analog peptide vaccine, WT1 126-134 peptide vaccine, tositumomab, autologous human tumor-derived HSPPC-96, and veltuzumab. Additional immunotherapy agents includes using cancer vaccines based upon the genetic makeup of an individual patient's tumor, such as lymphoma vaccine example is GTOP-99 (MyVax®).
  • Examples of chemotherapy agents for treating lymphoma or leukemia include aldesleukin, alvocidib, antineoplaston AS2-1, antineoplaston A10, anti-thymocyte globulin, amifostine trihydrate, aminocamptothecin, arsenic trioxide, beta alethine, Bcl-2 family protein inhibitor ABT-263, BMS-345541, bortezomib (Velcade®), bryostatin 1, busulfan, carboplatin, campath-1H, CC-5103, carmustine, caspofungin acetate, clofarabine, cisplatin, Cladribine (Leustarin), Chlorambucil (Leukeran), Curcumin, cyclosporine, Cyclophosphamide (Cyloxan, Endoxan, Endoxana, Cyclostin), cytarabine, denileukin diftitox, dexamethasone, DT PACE, docetaxel, dolastatin 10, Doxorubicin (Adriamycin®, Adriblastine), doxorubicin hydrochloride, enzastaurin, epoetin alfa, etoposide, Everolimus (RAD001), fenretinide, filgrastim, melphalan, mesna, Flavopiridol, Fludarabine (Fludara), Geldanamycin (17-AAG), ifosfamide, irinotecan hydrochloride, ixabepilone, Lenalidomide (Revlimid®, CC-5013), lymphokine-activated killer cells, melphalan, methotrexate, mitoxantrone hydrochloride, motexafin gadolinium, mycophenolate mofetil, nelarabine, oblimersen (Genasense) Obatoclax (GX15-070), oblimersen, octreotide acetate, omega-3 fatty acids, oxaliplatin, paclitaxel, PD0332991, PEGylated liposomal doxorubicin hydrochloride, pegfilgrastim, Pentstatin (Nipent), perifosine, Prednisolone, Prednisone, R-roscovitine (Selicilib, CYC202), recombinant interferon alfa, recombinant interleukin-12, recombinant interleukin-11, recombinant flt3 ligand, recombinant human thrombopoietin, rituximab, sargramostim, sildenafil citrate, simvastatin, sirolimus, Styryl sulphones, tacrolimus, tanespimycin, Temsirolimus (CCl-779), Thalidomide, therapeutic allogeneic lymphocytes, thiotepa, tipifarnib, Velcade® (bortezomib or PS-341), Vincristine (Oncovin), vincristine sulfate, vinorelbine ditartrate, Vorinostat (SAHA), vorinostat, and FR (fludarabine, rituximab), CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone), CVP (cyclophosphamide, vincristine and prednisone), FCM (fludarabine, cyclophosphamide, mitoxantrone), FCR (fludarabine, cyclophosphamide, rituximab), hyperCVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone, methotrexate, cytarabine), ICE (iphosphamide, carboplatin and etoposide), MCP (mitoxantrone, chlorambucil, and prednisolone), R-CHOP (rituximab plus CHOP), R-CVP (rituximab plus CVP), R-FCM (rituximab plus FCM), R-ICE (rituximab-ICE), and R-MCP (Rituximab-MCP).
  • In some embodiments, the cancer is melanoma. Suitable agents for use in combination with the compounds described herein include, without limitation, dacarbazine (DTIC), optionally, along with other chemotherapy drugs such as carmustine (BCNU) and cisplatin; the "Dartmouth regimen", which consists of DTIC, BCNU, cisplatin and tamoxifen; a combination of cisplatin, vinblastine, and DTIC, temozolomide or YERVOY™. Compounds according to the invention may also be combined with immunotherapy drugs, including cytokines such as interferon alpha, interleukin 2, and tumor necrosis factor (TNF) in the treatment of melanoma.
  • Compounds described here may also be used in combination with vaccine therapy in the treatment of melanoma. Anti-melanoma vaccines are, in some ways, similar to the anti-virus vaccines which are used to prevent diseases caused by viruses such as polio, measles, and mumps. Weakened melanoma cells or parts of melanoma cells called antigens may be injected into a patient to stimulate the body's immune system to destroy melanoma cells.
  • Melanomas that are confined to the arms or legs may also be treated with a combination of agents including one or more compounds described herein, using a hyperthermic isolated limb perfusion technique. This treatment protocol temporarily separates the circulation of the involved limb from the rest of the body and injects high doses of chemotherapy into the artery feeding the limb, thus providing high doses to the area of the tumor without exposing internal organs to these doses that might otherwise cause severe side effects. Usually the fluid is warmed to 102° to 104° F. Melphalan is the drug most often used in this chemotherapy procedure. This can be given with another agent called tumor necrosis factor (TNF).
  • The therapeutic treatments can be supplemented or combined with any of the abovementioned therapies with stem cell transplantation or treatment. One example of modified approach is radioimmunotherapy, wherein a monoclonal antibody is combined with a radioisotope particle, such as indium In 111, yttrium Y 90, iodine 1-131. Examples of combination therapies include, but are not limited to, Iodine-131 tositumomab (Bexxar®), Yttrium-90 ibritumomab tiuxetan (Zevalin®), Bexxar® with CHOP.
  • Other therapeutic procedures include peripheral blood stem cell transplantation, autologous hematopoietic stem cell transplantation, autologous bone marrow transplantation, antibody therapy, biological therapy, enzyme inhibitor therapy, total body irradiation, infusion of stem cells, bone marrow ablation with stem cell support, in vitro-treated peripheral blood stem cell transplantation, umbilical cord blood transplantation, immunoenzyme technique, pharmacological study, low-LET cobalt-60 gamma ray therapy, bleomycin, conventional surgery, radiation therapy, and nonmyeloablative allogeneic hematopoietic stem cell transplantation.
    • Anti-HBV Combination Therapy
  • In certain embodiments, a compound of formula I for use in a method for treating or preventing an HBV infection in a human having or at risk of having the infection is provided, comprising administering to the human a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more (e.g., one, two, three, four, one or two, or one to three, or one to four) additional therapeutic agents. In one embodiment, a compound of formula I for use in a method for treating an HBV infection in a human having or at risk of having the infection is provided, comprising administering to the human a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more (e.g., one, two, three, four, one or two, or one to three, or one to four) additional therapeutic agents.
  • In certain embodiments, the present disclosure provides a compound of formula I for use in a method for treating an HBV infection, comprising administering to a patient in need thereof a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more additional therapeutic agents which are suitable for treating an HBV infection.
  • In one embodiment, pharmaceutical compositions comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with one or more (e.g., one, two, three, four, one or two, or one to three, or one to four) additional therapeutic agents, and a pharmaceutically acceptable carrier, diluent or excipient are provided.
  • In one embodiment, kits comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with one or more (e.g., one, two, three, four, one or two, or one to three, or one to four) additional therapeutic agents are provided.
  • In the above embodiments, the additional therapeutic agent may be an anti-HBV agent. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of HBV combination drugs, HBV DNA polymerase inhibitors, immunomodulators, toll-like receptor modulators (modulators of tlr1, tlr2, tlr3, tlr4, tlr5, tlr6, tlr7, tlr8, tlr9, tlr10, tlr11, tlr12 and tlr13), interferon alpha receptor ligands, hyaluronidase inhibitors, recombinant IL-7, hepatitis B surface antigen (HBsAg) inhibitors, compounds targeting hepatitis B core antigen (HbcAg), cyclophilin inhibitors , HBV therapeutic vaccines, HBV prophylactic vaccines, HBV viral entry inhibitors, NTCP (Na+-taurocholate cotransporting polypeptide) inhibitors, antisense oligonucleotide targeting viral mRNA, short interfering RNAs (siRNA), miRNA gene therapy agents, endonuclease modulators, inhibitors of ribonucleotide reductase, hepatitis B virus E antigen inhibitors, recombinant scavenger receptor A (SRA) proteins, Src kinase inhibitors, HBx inhibitors, cccDNA inhibitors, short synthetic hairpin RNAs (sshRNAs), HBV antibodies including HBV antibodies targeting the surface antigens of the hepatitis B virus and bispecific antibodies and "antibody-like" therapeutic proteins (such as DARTs®, Duobodies®, Bites®, XmAbs®, TandAbs ®, Fab derivatives), CCR2 chemokine antagonists, thymosin agonists, cytokines, nucleoprotein inhibitors (HBV core or capsid protein inhibitors), stimulators of retinoic acid-inducible gene 1, stimulators of NOD2, stimulators of NOD1, Arginase-1 inhibitors, STING agonists, PI3K inhibitors, lymphotoxin beta receptor activators, Natural Killer Cell Receptor 2B4 inhibitors, Lymphocyte-activation gene 3 inhibitors, CD160 inhibitors, cytotoxic T-lymphocyte-associated protein 4 inhibitors, CD137 inhibitors, Killer cell lectin-like receptor subfamily G member 1 inhibitors, TIM-3 inhibitors, B- and T-lymphocyte attenuator inhibitors, CD305 inhibitors, PD-1 inhibitors, PD-L1 inhibitors, PEG-Interferon Lambda, recombinant thymosin alpha-1, BTK inhibitors, modulators of TIGIT, modulators of CD47, modulators of SIRPalpha, modulators of ICOS, modulators of CD27, modulators of CD70, modulators of OX40, modulators of NKG2D, modulators of Tim-4, modulators of B7-H4, modulators of B7-H3, modulators of NKG2A, modulators of GITR, modulators of CD160, modulators of HEVEM, modulators of CD161, modulators of Axl, modulators of Mer, modulators of Tyro, gene modifiers or editors such as CRISPR (including CRISPR Cas9), zinc finger nucleases or synthetic nucleases (TALENs), Hepatitis B virus replication inhibitors compounds such as those disclosed in US20100143301 (Gilead Sciences), US20110098248 (Gilead Sciences), US20090047249 (Gilead Sciences), US8722054 (Gilead Sciences), US20140045849 (Janssen), US20140073642 (Janssen), WO2014/056953 (Janssen), WO2014/076221 (Janssen), WO2014/128189 (Janssen), US20140350031 (Janssen), WO2014/023813 (Janssen), US20080234251 (Array Biopharma), US20080306050 (Array Biopharma), US20100029585 (Ventirx Pharma), US20110092485 (Ventirx Pharma), US20110118235 (Ventirx Pharma), US20120082658 (Ventirx Pharma), US20120219615 (Ventirx Pharma), US20140066432 (Ventirx Pharma), US20140088085 (VentirxPharma), US20140275167 (Novira therapeutics), US20130251673 (Novira therapeutics), US8513184 (Gilead Sciences), US20140030221 (Gilead Sciences), US20130344030 (Gilead Sciences), US20130344029 (Gilead Sciences), US20140343032 (Roche), WO2014037480 (Roche), US20130267517 (Roche), WO2014131847 (Janssen), WO2014033176 (Janssen), WO2014033170 (Janssen), WO2014033167 (Janssen), US20140330015 (Ono pharmaceutical), US20130079327 (Ono pharmaceutical), US20130217880 (Ono pharmaceutical), and other drugs for treating HBV, and combinations thereof.
  • In certain embodiments, the additional therapeutic is selected from the group consisting of HBV combination drugs, HBV DNA polymerase inhibitors, toll-like receptor 7 modulators, toll-like receptor 8 modulators, Toll-like receptor 7 and 8 modulators, Toll-like receptor 3 modulators, interferon alpha receptor ligands, HBsAg inhibitors, compounds targeting HbcAg, cyclophilin inhibitors, HBV therapeutic vaccines, HBV prophylactic vaccines, HBV viral entry inhibitors, NTCP inhibitors, antisense oligonucleotide targeting viral mRNA, short interfering RNAs (siRNA), hepatitis B virus E antigen inhibitors, HBx inhibitors, cccDNA inhibitors, HBV antibodies including HBV antibodies targeting the surface antigens of the hepatitis B virus, thymosin agonists, cytokines, nucleoprotein inhibitors (HBV core or capsid protein inhibitors), stimulators of retinoic acid-inducible gene 1, stimulators of NOD2, stimulators of NOD1, recombinant thymosin alpha-1, BTK inhibitors, and hepatitis B virus replication inhibitors, and combinations thereof.
  • In certain embodiments a compound disclosed herein is formulated as a tablet, which may optionally contain one or more other compounds useful for treating HBV. In certain embodiments, the tablet can contain another active ingredient for treating HBV, such as HBV DNA polymerase inhibitors, immunomodulators, toll-like receptor modulators (modulators of tlr1, tlr2, tlr3, tlr4, tlr5, tlr6, tlr7, tlr8, tlr9, tlr10, tlr11, tlr12 and tlr13), modulators of tlr7, modulators of tlr8, modulators of tlr7 and tlr8, interferon alpha receptor ligands, hyaluronidase inhibitors, hepatitis B surface antigen (HBsAg) inhibitors, compounds targeting hepatitis B core antigen (HbcAg), cyclophilin inhibitors , HBV viral entry inhibitors, NTCP (Na+-taurocholate cotransporting polypeptide) inhibitors, endonuclease modulators, inhibitors of ribonucleotide reductase, hepatitis B virus E antigen inhibitors, Src kinase inhibitors, HBx inhibitors, cccDNA inhibitors, CCR2 chemokine antagonists, thymosin agonists, nucleoprotein inhibitors (HBV core or capsid protein inhibitors), stimulators of retinoic acid-inducible gene 1, stimulators of NOD2, stimulators of NOD1, Arginase-1 inhibitors, STING agonists, PI3K inhibitors, lymphotoxin beta receptor activators, Natural Killer Cell Receptor 2B4 inhibitors, Lymphocyte-activation gene 3 inhibitors, CD160 inhibitors, cytotoxic T-lymphocyte-associated protein 4 inhibitors, CD137 inhibitors, Killer cell lectin-like receptor subfamily G member 1 inhibitors, TIM-3 inhibitors, B- and T-lymphocyte attenuator inhibitors, CD305 inhibitors, PD-1 inhibitors, PD-L1 inhibitors, BTK inhibitors, modulators of TIGIT, modulators of CD47, modulators of SIRP alpha, modulators of ICOS, modulators of CD27, modulators of CD70, modulators of OX40, modulators of NKG2D, modulators of Tim-4, modulators of B7-H4, modulators of B7-H3, modulators of NKG2A, modulators of GITR, modulators of CD160, modulators of HEVEM, modulators of CD161, modulators of Axl, modulators of Mer, modulators of Tyro, and Hepatitis B virus replication inhibitors, and combinations thereof.
  • In certain embodiments, such tablets are suitable for once daily dosing.
  • In certain embodiments, the additional therapeutic agent is selected from one or more of:
    1. (1) Combination drugs selected from the group consisting of tenofovir disoproxil fumarate + emtricitabine (TRUVADA®); adefovir + clevudine, ABX-203+lamivudine+PEG-IFNalpha, ABX-203+adefovir+PEG-IFNalpha and GBV-015;
    2. (2) HBV DNA polymerase inhibitors selected from the group consisting of besifovir, entecavir (Baraclude®), adefovir (Hepsera®), tenofovir disoproxil fumarate (Viread®), tenofovir alafenamide, tenofovir, tenofovir disoproxil, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, tenofovir dipivoxil , tenofovir dipivoxil fumarate, tenofovir octadecyloxyethyl ester, telbivudine (Tyzeka®), pradefovir, Clevudine, emtricitabine (Emtriva®), ribavirin, lamivudine (Epivir-HBV®), phosphazide, famciclovir, SNC-019754, FMCA, fusolin, AGX-1009 and metacavir;
    3. (3) Immunomodulators selected from the group consisting of rintatolimod, imidol hydrochloride, ingaron, dermaVir, plaquenil (hydroxychloroquine), proleukin, hydroxyurea, mycophenolate mofetil (MPA) and its ester derivative mycophenolate mofetil (MMF), WF-10, ribavirin, IL-12, polymer polyethyleneimine (PEI), Gepon, VGV-1, MOR-22, BMS-936559 and IR-103;
    4. (4) Toll-like receptor 7 modulators selected from the group consisting of GS-9620, GSK-2245035, imiquimod, resiquimod, DSR-6434, DSP-3025, IMO-4200, MCT-465, 3M-051, SB-9922, 3M-052, Limtop, TMX-30X, TMX-202 RG-7863 and RG-7795;
    5. (5) Toll-like receptor 8 modulators selected from the group consisting of motolimod, resiquimod, 3M-051, 3M-052, MCT-465, IMO-4200, VTX-763, VTX-1463;
    6. (6) Toll-like receptor 3 modulators selected from the group consisting of rintatolimod, poly-ICLC, MCT-465, MCT-475, Riboxxon, Riboxxim and ND-1.1;
    7. (7) Interferon alpha receptor ligands selected from the group consisting of interferon alpha-2b (Intron A®), pegylated interferon alpha-2a (Pegasys®), interferon alpha 1b (Hapgen®), Veldona, Infradure, Roferon-A, YPEG-interferon alfa-2a (YPEG-rhIFNalpha-2a), P-1101, Algeron, Alfarona, Ingaron (interferon gamma), rSIFN-co (recombinant super compound interferon), Ypeginterferon alfa-2b (YPEG-rhIFNalpha-2b), MOR-22, peginterferon alfa-2b (PEG-Intron®), Bioferon, Novaferon, Inmutag (Inferon), Multiferon®, interferon alfa-n1(Humoferon®), interferon beta-la (Avonex®), Shaferon, interferon alfa-2b (AXXO), Alfaferone, interferon alfa-2b (BioGeneric Pharma), interferon-alpha 2 (CJ), Laferonum, VIPEG, BLAUFERON-B, BLAUFERON-A, Intermax Alpha, Realdiron, Lanstion, Pegaferon, PDferon-B PDferon-B, interferon alfa-2b (IFN, Laboratorios Bioprofarma), alfainterferona 2b, Kalferon, Pegnano, Feronsure, PegiHep, interferon alfa 2b (Zydus-Cadila), Optipeg A, Realfa 2B, Reliferon, interferon alfa-2b (Amega), interferon alfa-2b (Virchow), peginterferon alfa-2b (Amega), Reaferon-EC, Proquiferon, Uniferon, Urifron, interferon alfa-2b (Changchun Institute of Biological Products), Anterferon, Shanferon, Layfferon, Shang Sheng Lei Tai, INTEFEN, SINOGEN, Fukangtai, Pegstat, rHSA-IFN alpha-2b and Interapo (Interapa);
    8. (8) Hyaluronidase inhibitors selected from the group consisting of astodrimer;
    9. (9) Modulators of IL-10;
    10. (10) HBsAg inhibitors selected from the group consisting of HBF-0259, PBHBV-001, PBHBV-2-15, PBHBV-2-1, REP 9AC, REP-9C and REP 9AC';
    11. (11) Toll like receptor 9 modulators selected from CYT003;
    12. (12) Cyclophilin inhibitors selected from the group consisting of OCB-030, SCY-635 and NVP-018;
    13. (13) HBV Prophylactic vaccines selected from the group consisting of Hexaxim, Heplisav, Mosquirix, DTwP-HBV vaccine, Bio-Hep-B, D/T/P/HBV/M (LBVP-0101; LBVW-0101), DTwP-Hepb-Hib-IPV vaccine, Heberpenta L, DTwP-HepB-Hib, V-419, CVI-HBV-001, Tetrabhay, hepatitis B prophylactic vaccine (Advax Super D), Hepatrol-07, GSK-223192A, Engerix B®, recombinant hepatitis B vaccine (intramuscular, Kangtai Biological Products), recombinant hepatitis B vaccine (Hansenual polymorpha yeast, intramuscular, Hualan Biological Engineering), Bimmugen, Euforavac, Eutravac, anrix-DTaP-IPV-Hep B, Infanrix-DTaP-IPV-Hep B-Hib, Pentabio Vaksin DTP-HB-Hib, Comvac 4, Twinrix, Euvax-B, Tritanrix HB, Infanrix Hep B, Comvax, DTP-Hib-HBV vaccine, DTP-HBV vaccine, Yi Tai, Heberbiovac HB, Trivac HB, GerVax, DTwP-Hep B-Hib vaccine, Bilive, Hepavax-Gene, SUPERVAX, Comvac5, Shanvac-B, Hebsulin, Recombivax HB, Revac B mcf, Revac B+, Fendrix, DTwP-HepB-Hib, DNA-001, Shan6, rhHBsAG vaccine, and DTaP-rHB-Hib vaccine;
    14. (14) HBV Therapeutic vaccines selected from the group consisting of HBsAG-HBIG complex, Bio-Hep-B, NASVAC, abi-HB (intravenous), ABX-203, Tetrabhay, GX-110E, GS-4774, peptide vaccine (epsilonPA-44), Hepatrol-07, NASVAC (NASTERAP), IMP-321, BEVAC, Revac B mcf, Revac B+, MGN-1333, KW-2, CVI-HBV-002, AltraHepB, VGX-6200, FP-02, TG-1050, NU-500, HBVax, im/TriGrid/antigen vaccine, Mega-CD40L-adjuvanted vaccine, HepB-v, NO-1800, recombinant VLP-based therapeutic vaccine (HBV infection, VLP Biotech), AdTG-17909, AdTG-17910 AdTG-18202, ChronVac-B, and Lm HBV;
    15. (15) HBV viral entry inhibitor selected from the group consisting of Myrcludex B;
    16. (16) Antisense oligonucleotide targeting viral mRNA selected from the group consisting of ISIS-HBVRx;
    17. (17) Short interfering RNAs (siRNA) selected from the group consisting of TKM-HBV (TKM-HepB), ALN-HBV, SR-008, ddRNAi and ARC-520;
    18. (18) Endonuclease modulators selected from the group consisting of PGN-514;
    19. (19) Inhibitors of ribonucleotide reductase selected from the group consisting of Trimidox;
    20. (20) Hepatitis B virus E antigen inhibitors selected from the group consisting of wogonin;
    21. (21) HBV antibodies targeting the surface antigens of the hepatitis B virus selected from the group consisting of GC-1102, XTL-17, XTL-19, XTL-001, KN-003 and fully human monoclonal antibody therapy (hepatitis B virus infection, Humabs BioMed);
    22. (22) HBV antibodies including monoclonal antibodies and polyclonal antibodies selected from the group consisting of Zutectra, Shang Sheng Gan Di, Uman Big (Hepatitis B Hyperimmune), Omri-Hep-B, Nabi-HB, Hepatect CP, HepaGam B, igantibe, Niuliva, CT-P24, hepatitis B immunoglobulin (intravenous, pH4, HBV infection, Shanghai RAAS Blood Products) and Fovepta (BT-088);
    23. (23) CCR2 chemokine antagonists selected from the group consisting of propagermanium;
    24. (24) Thymosin agonists selected from the group consisting of Thymalfasin;
    25. (25) Cytokines selected from the group consisting of recombinant IL-7, CYT-107, interleukin-2 (IL-2, Immunex); recombinant human interleukin-2 (Shenzhen Neptunus) and celmoleukin;
    26. (26) Nucleoprotein inhibitors (HBV core or capsid protein inhibitors) selected from the group consisting ofNVR-1221, NVR-3778, BAY 41-4109, morphothiadine mesilate and DVR-23;
    27. (27) Stimulators of retinoic acid-inducible gene 1 selected from the group consisting of SB-9200, SB-40, SB-44, ORI-7246, ORI-9350, ORI-7537, ORI-9020, ORI-9198 and ORI-7170;
    28. (28) Stimulators of NOD2 selected from the group consisting of SB-9200;
    29. (29) Recombinant thymosin alpha-1 selected from the group consisting of NL-004 and PEGylated thymosin alpha 1;
    30. (30) Hepatitis B virus replication inhibitors selected from the group consisting of isothiafludine, IQP-HBV, RM-5038 and Xingantie;
    31. (31) PI3K inhibitors selected from the group consisting of idelalisib, AZD-8186, buparlisib, CLR-457, pictilisib, neratinib, rigosertib, rigosertib sodium, EN-3342, TGR-1202, alpelisib, duvelisib, UCB-5857, taselisib, XL-765, gedatolisib, VS-5584, copanlisib, CAI orotate, perifosine, RG-7666, GSK-2636771, DS-7423, panulisib, GSK-2269557, GSK-2126458, CUDC-907, PQR-309, INCB-040093, pilaralisib, BAY-1082439, puquitinib mesylate, SAR-245409, AMG-319, RP-6530, ZSTK-474, MLN-1117, SF-1126, RV-1729, sonolisib, LY-3023414, SAR-260301 and CLR-1401;
    32. (32) cccDNA inhibitors selected from the group consisting of BSBI-25;
    33. (33) PD-L1 inhibitors selected from the group consisting of MEDI-0680, RG-7446, durvalumab, KY-1003, KD-033, MSB-0010718C, TSR-042, ALN-PDL, STI-A1014 and BMS-936559;
    34. (34) PD-1 inhibitors selected from the group consisting of nivolumab, pembrolizumab, pidilizumab, BGB-108 and mDX-400;
    35. (35) BTK inhibitors selected from the group consisting of ACP-196, dasatinib, ibrutinib, PRN-1008, SNS-062, ONO-4059, BGB-3111, MSC-2364447, X-022, spebrutinib, TP-4207, HM-71224, KBP-7536 and AC-0025;
    36. (36) Other drugs for treating HBV selected from the group consisting of gentiopicrin (gentiopicroside), nitazoxanide, birinapant, NOV-205 (Molixan; BAM-205), Oligotide, Mivotilate, Feron, levamisole, Ka Shu Ning, Alloferon, WS-007, Y-101 (Ti Fen Tai), rSIFN-co, PEG-IIFNm, KW-3, BP-Inter-014, oleanolic acid, HepB-nRNA, cTP-5 (rTP-5), HSK-II-2, HEISCO-106-1, HEISCO-106, Hepbarna, IBPB-006IA, Hepuyinfen, DasKloster 0014-01, Jiangantai (Ganxikang), picroside, GA5 NM-HBV, DasKloster-0039, hepulantai, IMB-2613, TCM-800B, reduced glutathione and ZH-2N; and
    37. (37) The compounds disclosed in US20100143301 (Gilead Sciences), US20110098248 (Gilead Sciences), US20090047249 (Gilead Sciences), US8722054 (Gilead Sciences), US20140045849 (Janssen), US20140073642 (Janssen), WO2014/056953 (Janssen), WO2014/076221 (Janssen), WO2014/128189 (Janssen), US20140350031 (Janssen), WO2014/023813 (Janssen), US20080234251 (Array Biopharma), US20080306050 (Array Biopharma), US20100029585 (Ventirx Pharma), US20110092485 (Ventirx Pharma), US20110118235 (Ventirx Pharma), US20120082658 (Ventirx Pharma), US20120219615 (Ventirx Pharma), US20140066432 (Ventirx Pharma), US20140088085 (VentirxPharma), US20140275167 (Novira therapeutics), US20130251673 (Novira therapeutics), US8513184 (Gilead Sciences), US20140030221 (Gilead Sciences), US20130344030 (Gilead Sciences), US20130344029 (Gilead Sciences), US20140343032 (Roche), WO2014037480 (Roche), US20130267517 (Roche), WO2014131847 (Janssen), WO2014033176 (Janssen), WO2014033170 (Janssen), WO2014033167 (Janssen), US20140330015 (Ono pharmaceutical), US20130079327 (Ono pharmaceutical), and US20130217880 (Ono pharmaceutical).
  • In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with one, two, three, four or more additional therapeutic agents. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with two additional therapeutic agents. In other embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with three additional therapeutic agents. In further embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with four additional therapeutic agents. The one, two, three, four or more additional therapeutic agents can be different therapeutic agents selected from the same class of therapeutic agents, and/or they can be selected from different classes of therapeutic agents.
  • In a specific embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with an HBV DNA polymerase inhibitor. In another specific embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with an HBV DNA polymerase inhibitor and at least one additional therapeutic agent selected from the group consisting of: immunomodulators, toll-like receptor modulators (modulators of tlr1, tlr2, tlr3, tlr4, tlr5, tlr6, tlr7, tlr8, tlr9, tlr10, tlr11, tlr12 and tlr13), interferon alpha receptor ligands, hyaluronidase inhibitors, recombinant IL-7, HBsAg inhibitors, compounds targeting HbcAg, cyclophilin inhibitors , HBV therapeutic vaccines, HBV prophylactic vaccines HBV viral entry inhibitors, NTCP inhibitors, antisense oligonucleotide targeting viral mRNA, short interfering RNAs (siRNA), miRNA gene therapy agents, endonuclease modulators, inhibitors of ribonucleotide reductase, Hepatitis B virus E antigen inhibitors, recombinant scavenger receptor A (SRA) proteins, src kinase inhibitors, HBx inhibitors, cccDNA inhibitors, short synthetic hairpin RNAs (sshRNAs), HBV antibodies including HBV antibodies targeting the surface antigens of the hepatitis B virus and bispecific antibodies and "antibody-like" therapeutic proteins (such as DARTs®, Duobodies®, Bites®, XmAbs®, TandAbs ®, Fab derivatives), CCR2 chemokine antagonists, thymosin agonists, cytokines, nucleoprotein inhibitors (HBV core or capsid protein inhibitors), stimulators of retinoic acid-inducible gene 1, stimulators of NOD2, stimulators of NOD1, Arginase-1 inhibitors, STING agonists, PI3K inhibitors, lymphotoxin beta receptor activators, Natural Killer Cell Receptor 2B4 inhibitors, Lymphocyte-activation gene 3 inhibitors, CD160 inhibitors, cytotoxic T-lymphocyte-associated protein 4 inhibitors, CD137 inhibitors, Killer cell lectin-like receptor subfamily G member 1 inhibitors, TIM-3 inhibitors, B- and T-lymphocyte attenuator inhibitors, CD305 inhibitors, PD-1 inhibitors, PD-L1 inhibitors, PEG-Interferon Lambda, recombinant thymosin alpha-1, BTK inhibitors, modulators of TIGIT, modulators of CD47, modulators of SIRPalpha, modulators of ICOS, modulators of CD27, modulators of CD70, modulators of OX40, modulators of NKG2D, modulators of Tim-4, modulators of B7-H4, modulators of B7-H3, modulators of NKG2A, modulators of GITR, modulators of CD160, modulators of HEVEM, modulators of CD161, modulators of Axl, modulators of Mer, modulators of Tyro, gene modifiers or editors such as CRISPR (including CRISPR Cas9), zinc finger nucleases or synthetic nucleases (TALENs), and Hepatitis B virus replication inhibitors.
  • In another specific embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with an HBV DNA polymerase inhibitor and at least a second additional therapeutic agent selected from the group consisting of: immunomodulators, toll-like receptor modulators (modulators of tlr1, tlr2, tlr3, tlr4, tlr5, tlr6, tlr7, tlr8, tlr9, tlr10, tlr11, tlr12 and tlr13), HBsAg inhibitors, HBV therapeutic vaccines, HBV antibodies including HBV antibodies targeting the surface antigens of the hepatitis B virus and bispecific antibodies and "antibody-like" therapeutic proteins (such as DARTs®, Duobodies®, Bites®, XmAbs®, TandAbs ®, Fab derivatives), cyclophilin inhibitors, stimulators of retinoic acid-inducible gene 1, PD-1 inhibitors, PD-L1 inhibitors, Arginase-1 inhibitors, PI3K inhibitors and stimulators of NOD2.
  • In another specific embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with an HBV DNA polymerase inhibitor and at least a second additional therapeutic agent selected from the group consisting of: HBV viral entry inhibitors, NTCP inhibitors, HBx inhibitors, cccDNA inhibitors, HBV antibodies targeting the surface antigens of the hepatitis B virus, short interfering RNAs (siRNA), miRNA gene therapy agents, short synthetic hairpin RNAs (sshRNAs), and nucleoprotein inhibitors (HBV core or capsid protein inhibitors).
  • In another specific embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with an HBV DNA polymerase inhibitor, one or two additional therapeutic agents selected from the group consisting of: immunomodulators, toll-like receptor modulators (modulators of tlr1, tlr2, tlr3, tlr4, tlr5, tlr6, tlr7, tlr8, tlr9, tlr10, tlr11, tlr12 and tlr13), HBsAg inhibitors, HBV therapeutic vaccines, HBV antibodies including HBV antibodies targeting the surface antigens of the hepatitis B virus and bispecific antibodies and "antibody-like" therapeutic proteins (such as DARTs®, Duobodies®, Bites®, XmAbs®, TandAbs ®, Fab derivatives), cyclophilin inhibitors, stimulators of retinoic acid-inducible gene 1, PD-1 inhibitors, PD-L1 inhibitors, Arginase-1 inhibitors, PI3K inhibitors and stimulators of NOD2, and one or two additional therapeutic agents selected from the group consisting of: HBV viral entry inhibitors, NTCP inhibitors, HBx inhibitors, cccDNA inhibitors, HBV antibodies targeting the surface antigens of the hepatitis B virus, short interfering RNAs (siRNA), miRNA gene therapy agents, short synthetic hairpin RNAs (sshRNAs), and nucleoprotein inhibitors (HBV core or capsid protein inhibitors).
  • In a particular embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with one, two, three, four or more additional therapeutic agents selected from adefovir (Hepsera®), tenofovir disoproxil fumarate + emtricitabine (TRUVADA®), tenofovir disoproxil fumarate (Viread®), entecavir (Baraclude®), lamivudine (Epivir-HBV®), tenofovir alafenamide, tenofovir, tenofovir disoproxil, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, telbivudine (Tyzeka®), Clevudine®, emtricitabine (Emtriva®), peginterferon alfa-2b (PEG-Intron®), Multiferon®, interferon alpha 1b (Hapgen®), interferon alpha-2b (Intron A®), pegylated interferon alpha-2a (Pegasys®), interferon alfa-n1(Humoferon®), ribavirin, interferon beta-la (Avonex®), Bioferon, Ingaron, Inmutag (Inferon), Algeron, Roferon-A, Oligotide, Zutectra, Shaferon, interferon alfa-2b (AXXO), Alfaferone, interferon alfa-2b (BioGeneric Pharma), Feron, interferon-alpha 2 (CJ), BEVAC, Laferonum, VIPEG, BLAUFERON-B, BLAUFERON-A, Intermax Alpha, Realdiron, Lanstion, Pegaferon, PDferon-B, interferon alfa-2b (IFN, Laboratorios Bioprofarma), alfainterferona 2b, Kalferon, Pegnano, Feronsure, PegiHep, interferon alfa 2b (Zydus-Cadila), Optipeg A, Realfa 2B, Reliferon, interferon alfa-2b (Amega), interferon alfa-2b (Virchow), peginterferon alfa-2b (Amega), Reaferon-EC, Proquiferon, Uniferon, Urifron, interferon alfa-2b (Changchun Institute of Biological Products), Anterferon, Shanferon, MOR-22, interleukin-2 (IL-2, Immunex), recombinant human interleukin-2 (Shenzhen Neptunus), Layfferon, Ka Shu Ning, Shang Sheng Lei Tai, INTEFEN, SINOGEN, Fukangtai, Alloferon and celmoleukin;
  • In a particular embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with entecavir (Baraclude®), adefovir (Hepsera®), tenofovir disoproxil fumarate (Viread®), tenofovir alafenamide, tenofovir, tenofovir disoproxil, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, telbivudine (Tyzeka®) or lamivudine (Epivir-HBV®).
  • In a particular embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with entecavir (Baraclude®), adefovir (Hepsera®), tenofovir disoproxil fumarate (Viread®), tenofovir alafenamide hemifumarate, telbivudine (Tyzeka®) or lamivudine (Epivir-HBV®).
  • In a particular embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with a first additional therapeutic agent selected from the group consisting of: entecavir (Baraclude®), adefovir (Hepsera®), tenofovir disoproxil fumarate (Viread®), tenofovir alafenamide, tenofovir, tenofovir disoproxil, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, telbivudine (Tyzeka®) or lamivudine (Epivir-HBV®) and at least a second additional therapeutic agent selected from the group consisting of immunomodulators, toll-like receptor modulators (modulators of tlr1, tlr2, tlr3, tlr4, tlr5, tlr6, tlr7, tlr8, tlr9, tlr10, tlr11, tlr12 and tlr13), interferon alpha receptor ligands, hyaluronidase inhibitors, recombinant IL-7, HBsAg inhibitors, compounds targeting HbcAg, cyclophilin inhibitors , HBV Therapeutic vaccines, HBV prophylactic vaccines, HBV viral entry inhibitors, NTCP inhibitors, antisense oligonucleotide targeting viral mRNA, short interfering RNAs (siRNA), miRNA gene therapy agents, endonuclease modulators, inhibitors of ribonucleotide reductase, Hepatitis B virus E antigen inhibitors, recombinant scavenger receptor A (SRA) proteins, src kinase inhibitors, HBx inhibitors, cccDNA inhibitors, short synthetic hairpin RNAs (sshRNAs), HBV antibodies including HBV antibodies targeting the surface antigens of the hepatitis B virus and bispecific antibodies and "antibody-like" therapeutic proteins (such as DARTs®, Duobodies®, Bites®, XmAbs®, TandAbs ®, Fab derivatives), CCR2 chemokine antagonists, thymosin agonists, cytokines, nucleoprotein inhibitors (HBV core or capsid protein inhibitors), stimulators of retinoic acid-inducible gene 1, stimulators of NOD2, stimulators of NOD1, recombinant thymosin alpha-1, Arginase-1 inhibitors, STING agonists, PI3K inhibitors, lymphotoxin beta receptor activators, Natural Killer Cell Receptor 2B4 inhibitors, Lymphocyte-activation gene 3 inhibitors, CD160 inhibitors, cytotoxic T-lymphocyte-associated protein 4 inhibitors, CD137 inhibitors, Killer cell lectin-like receptor subfamily G member 1 inhibitors, TIM-3 inhibitors, B- and T-lymphocyte attenuator inhibitors, CD305 inhibitors, PD-1 inhibitors, PD-L1 inhibitors, PEG-Interferon Lambd, BTK inhibitors, modulators of TIGIT, modulators of CD47, modulators of SIRPalpha, modulators of ICOS, modulators of CD27, modulators of CD70, modulators of OX40, modulators of NKG2D, modulators of Tim-4, modulators of B7-H4, modulators of B7-H3, modulators of NKG2A, modulators of GITR, modulators of CD160, modulators of HEVEM, modulators of CD161, modulators of Axl, modulators of Mer, modulators of Tyro, gene modifiers or editors such as CRISPR (including CRISPR Cas9), zinc finger nucleases or synthetic nucleases (TALENs), a and Hepatitis B virus replication inhibitors.
  • In a particular embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with a first additional therapeutic agent selected from the group consisting of: entecavir (Baraclude®), adefovir (Hepsera®), tenofovir disoproxil fumarate (Viread®), tenofovir alafenamide, tenofovir, tenofovir disoproxil, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, telbivudine (Tyzeka®) or lamivudine (Epivir-HBV®) and at least a second additional therapeutic agent selected from the group consisting of peginterferon alfa-2b (PEG-Intron®), Multiferon®, interferon alpha 1b (Hapgen®), interferon alpha-2b (Intron A®), pegylated interferon alpha-2a (Pegasys®), interferon alfa-n1(Humoferon®), ribavirin, interferon beta-1a (Avonex®), Bioferon, Ingaron, Inmutag (Inferon), Algeron, Roferon-A, Oligotide, Zutectra, Shaferon, interferon alfa-2b (AXXO), Alfaferone, interferon alfa-2b (BioGeneric Pharma), Feron, interferon-alpha 2 (CJ), BEVAC, Laferonum, VIPEG, BLAUFERON-B, BLAUFERON-A, Intermax Alpha, Realdiron, Lanstion, Pegaferon, PDferon-B, interferon alfa-2b (IFN, Laboratorios Bioprofarma), alfainterferona 2b, Kalferon, Pegnano, Feronsure, PegiHep, interferon alfa 2b (Zydus-Cadila), Optipeg A, Realfa 2B, Reliferon, interferon alfa-2b (Amega), interferon alfa-2b (Virchow), peginterferon alfa-2b (Amega), Reaferon-EC, Proquiferon, Uniferon, Urifron, interferon alfa-2b (Changchun Institute of Biological Products), Anterferon, Shanferon, MOR-22, interleukin-2 (IL-2, Immunex), recombinant human interleukin-2 (Shenzhen Neptunus), Layfferon, Ka Shu Ning, Shang Sheng Lei Tai, INTEFEN, SINOGEN, Fukangtai, Alloferon and celmoleukin;
  • In a particular embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with a first additional therapeutic agent selected from the group consisting of: entecavir (Baraclude®), adefovir (Hepsera®), tenofovir disoproxil fumarate (Viread®), tenofovir alafenamide, tenofovir, tenofovir disoproxil, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, telbivudine (Tyzeka®) or lamivudine (Epivir-HBV®) and at least a second additional therapeutic agent selected from the group consisting of immunomodulators, toll-like receptor modulators (modulators of tlr1, tlr2, tlr3, tlr4, tlr5, tlr6, tlr7, tlr8, tlr9, tlr10, tlr11, tlr12 and tlr13), HBsAg inhibitors, HBV therapeutic vaccines, HBV antibodies including HBV antibodies targeting the surface antigens of the hepatitis B virus and bispecific antibodies and "antibody-like" therapeutic proteins (such as DARTs®, Duobodies®, Bites®, XmAbs®, TandAbs ®, Fab derivatives), cyclophilin inhibitors, stimulators of retinoic acid-inducible gene 1, Arginase-1 inhibitors, PI3K inhibitors, PD-1 inhibitors, PD-L1 inhibitors and stimulators of NOD2.
  • In a particular embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with a first additional therapeutic agent selected from the group consisting of: entecavir (Baraclude®), adefovir (Hepsera®), tenofovir disoproxil fumarate (Viread®), tenofovir alafenamide, tenofovir, tenofovir disoproxil, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, telbivudine (Tyzeka®) or lamivudine (Epivir-HBV®) and at least a second additional therapeutic agent selected from the group consisting of HBV viral entry inhibitors, NTCP inhibitors, HBx inhibitors, cccDNA inhibitors, HBV antibodies targeting the surface antigens of the hepatitis B virus, short interfering RNAs (siRNA), miRNA gene therapy agents, short synthetic hairpin RNAs (sshRNAs), and nucleoprotein inhibitors (HBV core or capsid protein inhibitors).
  • In a particular embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with a first additional therapeutic agent selected from the group consisting of: entecavir (Baraclude®), adefovir (Hepsera®), tenofovir disoproxil fumarate (Viread®), tenofovir alafenamide, tenofovir, tenofovir disoproxil, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, telbivudine (Tyzeka®) or lamivudine (Epivir-HBV®), one or two additional therapeutic agents selected from the group consisting of: immunomodulators, toll-like receptor modulators (modulators of tlr1, tlr2, tlr3, tlr4, tlr5, tlr6, tlr7, tlr8, tlr9, tlr10, tlr11, tlr12 and tlr13), HBsAg inhibitors, HBV therapeutic vaccines, HBV antibodies including HBV antibodies targeting the surface antigens of the hepatitis B virus and bispecific antibodies and "antibody-like" therapeutic proteins (such as DARTs®, Duobodies®, Bites®, XmAbs®, TandAbs ®, Fab derivatives), cyclophilin inhibitors, stimulators of retinoic acid-inducible gene 1, PD-1 inhibitors, PD-L1 inhibitors, Arginase-1 inhibitors, PI3K inhibitors and stimulators of NOD2, and one or two additional therapeutic agents selected from the group consisting of: HBV viral entry inhibitors, NTCP inhibitors, HBx inhibitors, cccDNA inhibitors, HBV antibodies targeting the surface antigens of the hepatitis B virus, short interfering RNAs (siRNA), miRNA gene therapy agents, short synthetic hairpin RNAs (sshRNAs), and nucleoprotein inhibitors (HBV core or capsid protein inhibitors).
  • In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 5-30 mg tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 5-10; 5-15; 5-20; 5-25; 25-30; 20-30; 15-30; or 10-30 mg tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 10 mg tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 25 mg tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide. A compound as disclosed herein (e.g., a compound of formula (I)) may be combined with the agents provided herein in any dosage amount of the compound (e.g., from 50 mg to 500 mg of compound) the same as if each combination of dosages were specifically and individually listed.
  • In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 100-400 mg tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 100-150; 100-200, 100-250; 100-300; 100-350; 150-200; 150-250; 150-300; 150-350; 150-400; 200-250; 200-300; 200-350; 200-400; 250-350; 250-400; 350-400 or 300-400 mg tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 300 mg tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 250 mg tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 150 mg tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil. A compound as disclosed herein (e.g., a compound of formula (I)) may be combined with the agents provided herein in any dosage amount of the compound (e.g., from 50 mg to 500 mg of compound) the same as if each combination of dosages were specifically and individually listed.
  • In certain embodiments, when a compound disclosed herein is combined with one or more additional therapeutic agents as described above, the components of the composition are administered as a simultaneous or sequential regimen. When administered sequentially, the combination may be administered in two or more administrations.
  • In certain embodiments, a compound disclosed herein is combined with one or more additional therapeutic agents in a unitary dosage form for simultaneous administration to a patient, for example as a solid dosage form for oral administration.
  • In certain embodiments, a compound disclosed herein is administered with one or more additional therapeutic agents. Co-administration of a compound disclosed herein with one or more additional therapeutic agents generally refers to simultaneous or sequential administration of a compound disclosed herein and one or more additional therapeutic agents, such that therapeutically effective amounts of the compound disclosed herein and one or more additional therapeutic agents are both present in the body of the patient.
  • Co-administration includes administration of unit dosages of the compounds disclosed herein before or after administration of unit dosages of one or more additional therapeutic agents, for example, administration of the compound disclosed herein within seconds, minutes, or hours of the administration of one or more additional therapeutic agents. For example, in some embodiments, a unit dose of a compound disclosed herein is administered first, followed within seconds or minutes by administration of a unit dose of one or more additional therapeutic agents. Alternatively, in other embodiments, a unit dose of one or more additional therapeutic agents is administered first, followed by administration of a unit dose of a compound disclosed herein within seconds or minutes. In some embodiments, a unit dose of a compound disclosed herein is administered first, followed, after a period of hours (e.g., 1-12 hours), by administration of a unit dose of one or more additional therapeutic agents. In other embodiments, a unit dose of one or more additional therapeutic agents is administered first, followed, after a period of hours (e.g., 1-12 hours), by administration of a unit dose of a compound disclosed herein.
    • Anti-HIV Combination Therapy
  • In certain embodiments, a compound of formula I for use in a method for treating or preventing an HIV infection in a human having or at risk of having the infection is provided, comprising administering to the human a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more (e.g., one, two, three, four, one or two, or one to three, or one to four) additional therapeutic agents. In one embodiment, a
    compound of formula I for use in a method for treating an HIV infection in a human having or at risk of having the infection is provided, comprising administering to the human a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more (e.g., one, two, three, four, one or two, or one to three, or one to four) additional therapeutic agents.
  • In certain embodiments, the present disclosure provides a compound of formula I for use in a method for treating an HIV infection, comprising administering to a patient in need thereof a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more additional therapeutic agents which are suitable for treating an HIV infection.
  • In one embodiment, pharmaceutical compositions comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with one or more (e.g., one, two, three, four, one or two, or one to three, or one to four) additional therapeutic agents, and a pharmaceutically acceptable carrier, diluent or excipient are provided.
  • In one embodiment, kits comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with one or more (e.g., one, two, three, four, one or two, or one to three, or one to four) additional therapeutic agents are provided.
  • In the above embodiments, the additional therapeutic agent may be an anti- HIV agent. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of HIV protease inhibitors, HIV non-nucleoside inhibitors of reverse transcriptase, HIV nucleoside or nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, entry inhibitors (e.g., CCR5 inhibitors, gp41 inhibitors (i.e., fusion inhibitors) and CD4 attachment inhibitors), CXCR4 inhibitors, gpl20 inhibitors, G6PD and NADH-oxidase inhibitors, compounds that target the HIV capsid ("capsid inhibitors"; e.g., capsid polymerization inhibitors or capsid disrupting compounds such as those disclosed in WO 2013/006738 (Gilead Sciences), US 2013/0165489 (University of Pennsylvania), and WO 2013/006792 (Pharma Resources), pharmacokinetic enhancers, and other drugs for treating HIV, and combinations thereof.
  • In further embodiments, the additional therapeutic agent is selected from one or more of:
    1. (1) HIV protease inhibitors selected from the group consisting of amprenavir, atazanavir, fosamprenavir, indinavir, lopinavir, ritonavir, nelfmavir, saquinavir, tipranavir, brecanavir, darunavir, TMC-126, TMC-114, mozenavir (DMP-450), JE-2147 (AG1776), L- 756423, RO0334649, KNI-272, DPC-681, DPC-684, GW640385X, DG17, PPL-100, DG35, and AG 1859;
    2. (2) HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase selected from the group consisting of capravirine, emivirine, delaviridine, efavirenz, nevirapine, (+) calanolide A, etravirine, GW5634, DPC-083, DPC-961, DPC-963, MIV-150, TMC-120, rilpivirene, BILR 355 BS, VRX 840773, lersivirine (UK-453061), RDEA806, KM023 and MK-1439;
    3. (3) HIV nucleoside or nucleotide inhibitors of reverse transcriptase selected from the group consisting of zidovudine, emtricitabine, didanosine, stavudine, zalcitabine, lamivudine, abacavir, abavavir sulfate, amdoxovir, elvucitabine, alovudine, MIV-210, ±- FTC, D-d4FC, emtricitabine, phosphazide, fozivudine tidoxil, apricitibine (AVX754), KP-1461, GS-9131 (Gilead Sciences) and fosalvudine tidoxil (formerly HDP 99.0003), tenofovir, tenofovir disoproxil fumarate, tenofovir alafenamide (Gilead Sciences), tenofovir alafenamide hemifumarate (Gilead Sciences), GS-9148 (Gilead Sciences), adefovir, adefovir dipivoxil, CMX-001 (Chimerix) or CMX-157 (Chimerix);
    4. (4) HIV integrase inhibitors selected from the group consisting of curcumin, derivatives of curcumin, chicoric acid, derivatives of chicoric acid, 3,5-dicaffeoylquinic acid, derivatives of 3,5-dicaffeoylquinic acid, aurintricarboxylic acid, derivatives of aurintricarboxylic acid, caffeic acid phenethyl ester, derivatives of caffeic acid phenethyl ester, tyrphostin, derivatives of tyrphostin, quercetin, derivatives of quercetin, S-1360, AR- 177, L-870812, and L-870810, raltegravir, BMS-538158, GSK364735C, BMS-707035, MK- 2048, BA 011, elvitegravir, dolutegravir and GSK-744;
    5. (5) HIV non-catalytic site, or allosteric, integrase inhibitors (NCINI) including, but not limited to, BI-224436, CX0516, CX05045, CX14442, compounds disclosed in WO 2009/062285 (Boehringer Ingelheim), WO 2010/130034 (Boehringer Ingelheim), WO 2013/159064 (Gilead Sciences), WO 2012/145728 (Gilead Sciences), WO 2012/003497 (Gilead Sciences), WO 2012/003498 (Gilead Sciences) each of which is incorporated by references in its entirety herein;
    6. (6) gp41 inhibitors selected from the group consisting of enfuvirtide, sifuvirtide, albuvirtide, FB006M, and TRI-1144;
    7. (7) the CXCR4 inhibitor AMD-070;
    8. (8) the entry inhibitor SP01A;
    9. (9) the gpl20 inhibitor BMS-488043;
    10. (10) the G6PD and NADH-oxidase inhibitor immunitin;
    11. (11) CCR5 inhibitors selected from the group consisting of aplaviroc, vicriviroc, maraviroc, cenicriviroc, PRO-140, INCB15050, PF-232798 (Pfizer), and CCR5mAb004;
    12. (12) CD4 attachment inhibitors selected from the group consisting of ibalizumab (TMB-355) and BMS-068 (BMS-663068);
    13. (13) pharmacokinetic enhancers selected from the group consisting of cobicistat and SPI-452; and
    14. (14) other drugs for treating HIV selected from the group consisting of BAS-100, SPI-452, REP 9, SP-01A, TNX-355, DES6, ODN-93, ODN-112, VGV-1, PA-457 (bevirimat), HRG214, VGX-410, KD-247, AMZ 0026, CYT 99007A-221 HIV, DEBIO-025, BAY 50-4798, MDX010 (ipilimumab), PBS 119, ALG 889, and PA- 1050040 (PA-040), and combinations thereof.
  • In certain embodiments, the additional therapeutic agent is a Toll-like receptor 8 modulator selected from the group consisting of motolimod, resiquimod, 3M-051, 3M-052, MCT-465, IMO-4200, VTX-763, VTX-1463 and those disclosed in US20140045849 (Janssen), US20140073642 (Janssen), WO2014/056953 (Janssen), WO2014/076221 (Janssen), WO2014/128189 (Janssen), US20140350031 (Janssen), WO2014/023813 (Janssen), US20080234251 (Array Biopharma), US20080306050 (Array Biopharma), US20100029585 (Ventirx Pharma), US20110092485 (Ventirx Pharma), US20110118235 (Ventirx Pharma), US20120082658 (Ventirx Pharma),
  • US20120219615 (Ventirx Pharma), US20140066432 (Ventirx Pharma), US20140088085 (VentirxPharma), US20140275167 (Novira therapeutics), US20130251673 (Novira therapeutics).
  • In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with one, two, three, four or more additional therapeutic agents. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with two additional therapeutic agents. In other embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with three additional therapeutic agents. In further embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with four additional therapeutic agents. The two, three, four or more additional therapeutic agents can be different therapeutic agents selected from the same class of therapeutic agents, or they can be selected from different classes of therapeutic agents. In a specific embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with an HIV nucleoside or nucleotide inhibitor of reverse transcriptase and an HIV non-nucleoside inhibitor of reverse transcriptase. In another specific embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, and an HIV protease inhibiting compound. In a further embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, an HIV non-nucleoside inhibitor of reverse transcriptase, and an HIV protease inhibiting compound. In an additional embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, an HIV non-nucleoside inhibitor of reverse transcriptase, and a pharmacokinetic enhancer. In another embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with two HIV nucleoside or nucleotide inhibitor of reverse transcriptase.
  • In a particular embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with abacavir sulfate, tenofovir, tenofovir disoproxil fumarate, tenofovir alafenamide, or tenofovir alafenamide hemifumarate.
  • In a particular embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with tenofovir, tenofovir disoproxil fumarate, tenofovir alafenamide, or tenofovir alafenamide hemifumarate.
  • In a particular embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with a first additional therapeutic agent selected from the group consisting of: abacavir sulfate, tenofovir, tenofovir disoproxil fumarate, tenofovir alafenamide, and tenofovir alafenamide hemifumarate and a second additional therapeutic agent selected from the group consisting of emtricitibine and lamivudine. In a particular embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with a first additional therapeutic agent selected from the group consisting of: tenofovir, tenofovir disoproxil fumarate, tenofovir alafenamide, and tenofovir alafenamide hemifumarate and a second additional therapeutic agent, wherein the second additional therapeutic agent is emtricitibine.
  • In certain embodiments, when a compound disclosed herein is combined with one or more additional therapeutic agents as described above, the components of the composition are administered as a simultaneous or sequential regimen. When administered sequentially, the combination may be administered in two or more administrations.
  • In certain embdoiments, a compound disclosed herein is combined with one or more additional therapeutic agents in a unitary dosage form for simultaneous administration to a patient, for example as a solid dosage form for oral administration.
  • In certain embodiments, a compound disclosed herein is administered with one or more additional therapeutic agents. Co-administration of a compound disclosed herein with one or more additional therapeutic agents generally refers to simultaneous or sequential administration of a compound disclosed herein and one or more additional therapeutic agents, such that therapeutically effective amounts of the compound disclosed herein and one or more additional therapeutic agents are both present in the body of the patient.
  • Co-administration includes administration of unit dosages of the compounds disclosed herein before or after administration of unit dosages of one or more additional therapeutic agents, for example, administration of the compound disclosed herein within seconds, minutes, or hours of the administration of one or more additional therapeutic agents. For example, in some embodiments, a unit dose of a compound disclosed herein is administered first, followed within seconds or minutes by administration of a unit dose of one or more additional therapeutic agents. Alternatively, in other embodiments, a unit dose of one or more additional therapeutic agents is administered first, followed by administration of a unit dose of a compound disclosed herein within seconds or minutes. In some embodiments, a unit dose of a compound disclosed herein is administered first, followed, after a period of hours (e.g., 1-12 hours), by administration of a unit dose of one or more additional therapeutic agents. In other embodiments, a unit dose of one or more additional therapeutic agents is administered first, followed, after a period of hours (e.g., 1-12 hours), by administration of a unit dose of a compound disclosed herein.
    • Kits
  • Provided herein are also kits that include a compound of Formula I, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, and suitable packaging. In one embodiment, a kit further includes instructions for use. In one aspect, a kit includes a compound of Formula I, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, and a label and/or instructions for use of the compounds in the treatment of the indications, including the diseases or conditions, described herein.
  • Provided herein are also articles of manufacture that include a compound described herein or pharmaceutically acceptable salts, or a mixture thereof in a suitable container. The container may be a vial, jar, ampoule, preloaded syringe, and intravenous bag.
    • Pharmaceutical Compositions and Modes of Administration
  • Compounds provided herein are usually administered in the form of pharmaceutical compositions. Thus, provides herein are also pharmaceutical compositions that contain one or more of the compounds described herein or pharmaceutically acceptable salts, isomer, or a mixture thereof and one or more pharmaceutically acceptable vehicles selected from carriers, adjuvants and excipients. Suitable pharmaceutically acceptable vehicles may include, for example, inert solid diluents and fillers, diluents, including sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers and adjuvants. Such compositions are prepared in a manner well known in the pharmaceutical art. See, e.g., Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa. 17th Ed. (1985); and Modern Pharmaceutics, Marcel Dekker, Inc. 3rd Ed. (G.S. Banker & C.T. Rhodes, Eds.).
  • The pharmaceutical compositions may be administered in either single or multiple doses. The pharmaceutical composition may be administered by various methods including, for example, rectal, buccal, intranasal and transdermal routes. In certain embodiments, the pharmaceutical composition may be administered by intraarterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, or as an inhalant.
  • One mode for administration is parenteral, for example, by injection. The forms in which the pharmaceutical compositions described herein may be incorporated for administration by injection include, for example, aqueous or oil suspensions, or emulsions, with sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or a sterile aqueous solution, and similar pharmaceutical vehicles.
  • Oral administration may be another route for administration of the compounds described herein. Administration may be via, for example, capsule or enteric coated tablets. In making the pharmaceutical compositions that include at least one compound described herein or pharmaceutically acceptable salts, isomer, or a mixture thereof, the active ingredient is usually diluted by an excipient and/or enclosed within such a carrier that can be in the form of a capsule, sachet, paper or other container. When the excipient serves as a diluent, it can be in the form of a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injectable solutions, and sterile packaged powders.
  • Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methyl cellulose. The formulations can additionally include lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl and propylhydroxy-benzoates; sweetening agents; and flavoring agents.
  • The compositions that include at least one compound described herein or pharmaceutically acceptable salts, or a mixture thereof can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the subject by employing procedures known in the art. Controlled release drug delivery systems for oral administration include osmotic pump systems and dissolutional systems containing polymer-coated reservoirs or drug-polymer matrix formulations. Examples of controlled release systems are given in U.S. Patent Nos. 3,845,770 ; 4,326,525 ; 4,902,514 ; and 5,616,345 . Another formulation for use in the methods of the present invention employs transdermal delivery devices ("patches"). Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds described herein in controlled amounts. The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, e.g., U.S. Patent Nos. 5,023,252 , 4,992,445 and 5,001,139 . Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.
  • For preparing solid compositions such as tablets, the principal active ingredient may be mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound described herein or pharmaceutically acceptable salts, or a mixture thereof. When referring to these preformulation compositions as homogeneous, the active ingredient may be dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.
  • The tablets or pills of the compounds described herein may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action, or to protect from the acid conditions of the stomach. For example, the tablet or pill can include an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer that serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.
  • Compositions for inhalation or insufflation may include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra. In some embodiments, the compositions are administered by the oral or nasal respiratory route for local or systemic effect. In other embodiments, compositions in pharmaceutically acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be inhaled directly from the nebulizing device or the nebulizing device may be attached to a facemask tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from devices that deliver the formulation in an appropriate manner.
    • Dosing
  • The specific dose level of a compound of the present application for any particular subject will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination and the severity of the particular disease in the subject undergoing therapy. For example, a dosage may be expressed as a number of milligrams of a compound described herein per kilogram of the subject's body weight (mg/kg). Dosages of between about 0.1 and 150 mg/kg may be appropriate. In some embodiments, about 0.1 and 100 mg/kg may be appropriate. In other embodiments a dosage of between 0.5 and 60 mg/kg may be appropriate. Normalizing according to the subject's body weight is particularly useful when adjusting dosages between subjects of widely disparate size, such as occurs when using the drug in both children and adult humans or when converting an effective dosage in a non-human subject such as dog to a dosage suitable for a human subject.
  • The daily dosage may also be described as a total amount of a compound described herein administered per dose or per day. Daily dosage of a compound of Formula I may be between about 1 mg and 4,000 mg, between about 2,000 to 4,000 mg/day, between about 1 to 2,000 mg/day, between about 1 to 1,000 mg/day, between about 10 to 500 mg/day, between about 20 to 500 mg/day, between about 50 to 300 mg/day, between about 75 to 200 mg/day, or between about 15 to 150 mg/day.
  • When administered orally, the total daily dosage for a human subject may be between 1 mg and 1,000 mg, between about 10-500 mg/day, between about 50-300 mg/day, between about 75-200 mg/day, or between about 100-150 mg/day.
  • The compounds of the present application or the compositions thereof may be administered once, twice, three, or four times daily, using any suitable mode described above. Also, administration or treatment with the compounds may be continued for a number of days; for example, commonly treatment would continue for at least 7 days, 14 days, or 28 days, for one cycle of treatment. Treatment cycles are well known in cancer chemotherapy, and are frequently alternated with resting periods of about 1 to 28 days, commonly about 7 days or about 14 days, between cycles. The treatment cycles, in other embodiments, may also be continuous.
  • In a particular embodiment of a compound of formula I for use in a method, the method comprises administering to the
    subject an initial daily dose of about 1 to 500 mg of a compound described herein and increasing the dose by increments until clinical efficacy is achieved. Increments of about 5, 10, 25, 50, or 100 mg can be used to increase the dose. The dosage can be increased daily, every other day, twice per week, or once per week.
    • Synthesis of the Compounds of Formula I
  • The compounds may be prepared using the methods disclosed herein and routine modifications thereof, which will be apparent given the disclosure herein and methods well known in the art. Conventional and well-known synthetic methods may be used in addition to the teachings herein. The synthesis of typical compounds described herein may be accomplished as described in the following examples. If available, reagents may be purchased commercially, e.g., from Sigma Aldrich or other chemical suppliers.
    • General Synthesis
  • Typical embodiments of compounds described herein may be synthesized using the general reaction schemes described below. It will be apparent given the description herein that the general schemes may be altered by substitution of the starting materials with other materials having similar structures to result in products that are correspondingly different. Descriptions of syntheses follow to provide numerous examples of how the starting materials may vary to provide corresponding products. Given a desired product for which the substituent groups are defined, the necessary starting materials generally may be determined by inspection. Starting materials are typically obtained from commercial sources or synthesized using published methods. For synthesizing compounds which are embodiments described in the present disclosure, inspection of the structure of the compound to be synthesized will provide the identity of each substituent group. The identity of the final product will generally render apparent the identity of the necessary starting materials by a simple process of inspection, given the examples herein. In general, compounds described herein are typically stable and isolatable at room temperature and pressure.
    • Synthetic Reaction Parameters
  • The compounds of this disclosure can be prepared from readily available starting materials using, for example, the following general methods and procedures. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures.
  • Additionally, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. Suitable protecting groups for various functional groups as well as suitable conditions for protecting and deprotecting particular functional groups are well known in the art. For example, numerous protecting groups are described in T. W. Greene and G. M. Wuts (1999) Protecting Groups in Organic Synthesis, 3rd Edition, Wiley, New York, and references cited therein.
  • Furthermore, the compounds of this disclosure may contain one or more chiral centers. Accordingly, if desired, such compounds can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereomers or as stereoisomer-enriched mixtures. All such stereoisomers (and enriched mixtures) are included within the scope of this disclosure, unless otherwise indicated. Pure stereoisomers (or enriched mixtures) may be prepared using, for example, optically active starting materials or stereoselective reagents well-known in the art. Alternatively, racemic mixtures of such compounds can be separated using, for example, chiral column chromatography, chiral resolving agents, and the like.
  • The starting materials for the following reactions are generally known compounds or can be prepared by known procedures or obvious modifications thereof. For example, many of the starting materials are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA), Bachem (Torrance, California, USA), Emka-Chemce or Sigma (St. Louis, Missouri, USA). Others may be prepared by procedures or obvious modifications thereof, described in standard reference texts such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-15 (John Wiley, and Sons, 1991), Rodd's Chemistry of Carbon Compounds, Volumes 1-5, and Supplementals (Elsevier Science Publishers, 1989) organic Reactions, Volumes 1-40 (John Wiley, and Sons, 1991), March's Advanced Organic Chemistry, (John Wiley, and Sons, 5th Edition, 2001), and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989).
  • The terms "solvent", "inert organic solvent", or "inert solvent" refer to a solvent inert under the conditions of the reaction being described in conjunction therewith (including, for example, benzene, toluene, acetonitrile, tetrahydrofuran ("THF"), dimethylformamide ("DMF"), chloroform, methylene chloride (or dichloromethane), diethyl ether, methanol, and the like). Unless specified to the contrary, the solvents used in the reactions of the present invention are inert organic solvents, and the reactions are carried out under an inert gas, preferably nitrogen.
  • The term "q.s." means adding a quantity sufficient to achieve a stated function, e.g., to bring a solution to the desired volume (i.e., 100%).
    • Compounds of Formula I
  • The compounds of Formula I may prepared by first providing the substituted imidazo[4,5-b]pyridine or benzimidazole core, and optionally further modifying the core as desired to provide the substituents disclosed herein.
  • Scheme 1 shows the preparation of compounds of Formula I, where m, n, L, R1, R2a, R2b, and X are as defined herein, and R4 is
    Figure imgb0138
     as defined herein, or a functional group that is converted thereto using standard reaction conditions and protection/deprotection steps as required.
    Figure imgb0139
  • In Scheme 1, suitably substituted 1-a and 1-b are coupled and cyclized in a suitable solvent (e.g., formic acid, ethanol, etc.) at an elevated temperature (typically about 80-100 °C) to provide the imidazo[4,5-b]pyridine or benzimidazole core 1-c. 1-c is then converted to the corresponding thioamide 1-d using Lawesson's reagent (i.e., 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulfide) under standard conditions. 1-e is obtained by cyclization of the thioamide 1-d using hydroxylamine. Hydrolysis of 1-e to obtain compound 1-f is achieved by reaction with a suitable base (e.g., NaOH). Alternately, 1-c is transformed to compound 1-f using phosphorous pentachloride, followed by treatment with aqueous hydroxylamine.
  • Scheme 2 shows the synthesis of compounds of Formula I where Rt is hydrogen, and R1, R2a, R2b, and X are as defined herein.
    Figure imgb0140
  • In Scheme 2, 2-a is nitrated using fuming nitric acid to provide 2-b, which is then cyclized to provide C-2 unsubstituted imidazo[4,5-b]pyridine or benzimidazole 2-c under reducing conditions (e.g., zinc, iron, etc.). Amide 2-e is provided by reacting the corresponding ester 2-c with a suitable amine 2-d under standard amide bond forming reaction conditions, and is then converted to compounds of Formula I using the methods shown above in Scheme 1.
  • Scheme 3 shows the synthesis of compounds of Formula I where Rt is - NH2, and R1, R2a, R2b, and X are as defined herein.
    Figure imgb0141
  • In Scheme 3, 3-b is obtained by reaction of 3-a with cyanogen bromide. Amide 3-d is provided by reacting the corresponding ester 3-b with a suitable amine 3-c under standard amide bond forming reaction conditions, and is then converted to compounds of Formula I using the methods shown above in Scheme 1.
  • In certain embodiments, the process may comprise protection and deprotection/further modification of R4 (Scheme 1) to provide the desired
    Figure imgb0142
     group in the compound of Formula I. Scheme 4 shows an exemplary protection/deprotection or further modification to provide compounds of Formula I, where Rt, Rm, m, L, R1, R2a, R2b, and X are as defined herein.
    Figure imgb0143
  • In Scheme 4, suitably substituted 4-a can be protected to provide 4-b using a suitable proecting group PG, such as a silyl ether (see, e.g., T. W. Greene and G. M. Wuts (1999) Protecting Groups in Organic Synthesis, 3rd Edition, Wiley, New York, and references cited therein). 4-b is then converted to the corresponding thioamide 4-c and cyclized using hydroxylamine as shown above in Scheme 1 to provide 4-d. 4-d can then be coverted to compound 4-e by deprotectiona and optional further modification. For example, 4-d can be deprotected and converted to a suitable leaving group (e.g., a TMS-O- group) and then reacted with a suitable amine to provide compounds of formula 4-e where L is -NR3-. 4-e is then converted to compounds of Formula I using the methods shown above in Scheme 1.
  • Each of the intermediates in the above schemes may be isolated and/or purified prior to the subsequent step, or used in the next step without purification and/or isolation. It will also be appreciated that the addition of any substituent may result in the production of a number of isomeric products any or all of which may be isolated and purified using conventional techniques.
    • EXAMPLES
  • The following examples are included to demonstrate specific embodiments of the disclosure. It should be appreciated by those of skill in the art that the techniques disclosed in the examples which follow represent techniques discovered by the inventor to function well in the practice of the disclosure, and thus can be considered to constitute specific modes for its practice. List of Abbreviations and Acronyms
    Abbreviation Meaning
    % Percent
    °C Degree Celsius
    A2B Adenosine A2B receptor
    Ac Acetyl
    ACN/CH3CN/MeCN Acetonitrile
    ADME Absorption, distribution, metabolism and excretion
    AlMe3 Trimethylaluminum
    APECED Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy
    ASK Apoptosis signal-regulating kinase
    BAPN Beta-aminoproprionitrile
    BCNU Carmustine
    bicarb Bicarbonate
    br Broad
    BRD Bromodomain containing protein inhibitor
    BTK Bruton's tyrosine kinase
    BTK Bruton's tyrosine kinase
    CAS Chemical Abstract Service
    cccDNA Covalently closed circular DNA
    CCR C-C chemokine receptor
    CD Cluster of differentiation
    CHOP Cyclophosphamide
    CNS Central nervous system
    COPD Chronic obstructive pulmonary disease
    CREST Calcinosis, Raynaud's syndrome, esophageal dysmotility, sclerodactyly and telangiectasia
    CRISPR Clustered regularly interspaced short palindromic repeats
    CVP Cyclophosphamide, vincristine, prednisone
    d Doublet
    D Deuterium
    D.T. PACE Dexamethasone, thalidomide, cisplatin, Adriamycin®, cyclophosphamide, etoposide
    D/d Deuterium
    DABAL-Me3 Bis(trimethylaluminum)-DABCO® adduct
    DABCO® 1,4-Diazabicyclo[2.2.2]octane
    DCE Dichloroethane
    DCM/CH2Cl2 Dichloromethane/methylene chloride
    dd Doublet of doublets
    DDR Discoidin domain receptor
    DIPEA/DIEA N,N-Diisopropylethylamine
    DMF Dimethylformamide
    DMFO Difluoromethylornithine
    DMPK Drug metabolism and pharmacokinetics
    DMSO Dimethylsulfoxide
    DTIC Dacarbazine
    EC50 The half maximal effective concentration
    EDC 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide
    equiv/eq Equivalents
    Et Ethyl
    Et3N Triethylamine
    EtOAc/AcOEt Ethylacetate
    EtOH Ethanol
    F Fahrenheit
    Fab Fragment antigen-binding
    FBS Fetal bovine serum
    FCM Fludarabine, cyclophosphamide, mitoxantrone
    FCR Fludarabine, cyclophosphamide, rituximab
    FOLFIRI Fluorouracil, leucovorin, and irinotecan
    FR Fludarabine, rituximab
    g Grams
    GITR Glucocorticoid-induced TNFR-related protein
    Gp Glycoprotein
    h/hr Hours
    HATU (1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate)
    HbcAg Hepatitis B core antigen
    HBsAg Hepatitis B surface antigen
    HBV Hepatitis B virus
    HBx Hepatitis B viral protein
    HDAC Histone deacetylase
    hex Hexanes
    HOBt Hydroxybenzotriazole
    HPLC High pressure liquid chromatography
    hyperCVAD Hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone, methotrexate, cytarabine
    Hz Hertz
    ICE Iphosphamide, carboplatin, etoposide
    ICOS Inducible T-cell COStimulator
    IDH Isocitrate dehydrogenase
    IDO1 Indoleamine 2,3-dioxygenase 1
    IL Interleukin
    INCB24360 Epacadostat
    IUPAC International Union of Pure and Applied Chemistry
    J Coupling constant (MHz)
    JAK Janus kinase
    Kg/kg Kilogram
    LACA 1-Azetidine-2-carboxylic acid
    LCMS/LC-MS Liquid chromatography-mass spectrometry
    LET Linear energy transfer
    LOX Lysyl oxidase protein
    LOXL Lysyl oxidase-like protein
    M Molar
    m multiplet
    M+ Mass peak
    M+H Mass peak plus hydrogen
    MCP Mitoxantrone, chlorambucil, and prednisolone
    Me Methyl
    mg Milligram
    MHz Megahertz
    min/m Minute
    miRNA MicroRNA
    ml/mL Milliliter
    mM Millimolar
    MMF Ester derivative mycophenolate mofetil
    mmol Millimole
    MMP Matrix metalloprotease
    mol Mole
    MPA Mycophenolate mofetil
    MS Mass spectroscopy
    MS Multiple sclerosis
    N Normal
    NADH Nicotinamide adenine dinucleotide in reduced form
    NCINI Non-catalytic site, or allosteric, integrase inhibitors
    NCS N-Chlorosuccinimide
    ng Nanograms
    nM NanoMolar
    NMR Nuclear magnetic resonance
    NOD Nucleotide-binding oligomerization domain-containing protein
    NTCP Na+-taurocholate cotransporting polypeptide
    PD Programmed cell death
    PdCl2(dppf) [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II),
    PdCl2(PPh3)2 Bis(triphenylphosphine)palladium(II) dichloride
    PD-L Programmed death-ligand
    PEG Polyethylene glycol
    PEI Polymer polyethyleneimine
    PET Positron emission tomography
    Ph Phenyl
    PI3K Phosphoinositide 3-kinase
    PKC Protein kinase C
    prep Preparative
    q.s. Quantity sufficient to achieve a stated function
    RA Rheumatoid arthritis
    R-CHOP Rituximab-CHOP (Rituximab plus CHOP)
    R-CVP Rituximab-CVP (Rituximab plus CVP)
    Rf Retention factor
    R-FCM Rituximab plus FCM
    R-hyperCVAD Rituximab-hyperCVAD
    R-ICE Rituximab-ICE
    R-MCP Rituximab-MCP
    RPM Revolutions per minute
    rSIFN-co Recombinant super compound interferon
    RT/rt Room temperature
    s Second
    s Singlet
    SAHA Vorinostat
    sat. Saturated
    SEM 2-(Trimethylsilyl)ethoxymethyl
    SERMs Selective estrogen receptor modulators
    siRNA Short interfering RNAs
    SIRP Signal-regulatory protein
    SLE Systemic lupus erythematosus
    SPECT Single-photon emission computed tomography
    SRA Scavenger receptor A
    Src Proto-oncogene tyrosine-protein kinase
    sshRNAs Short synthetic hairpin RNAs
    STING Sequence To and withIN Graphics
    SYK Spleen tyrosine kinase
    t Triplet
    TALENs Transcription activator-like effector nucleases
    TBAF Tetra-n-butylammonium fluoride
    TCA Trichloroacetic acid
    TEA Triethylamine
    temp. Temperature
    TFA Trifluoroacetic acid
    THF Tetrahydrofuran
    TIGIT T cell immunoreceptor with Ig and ITIM domains
    TIM T-cell immunoglobulin and mucin domain
    TKM-HBV TKM-HepB
    Tlr Toll-like receptor modulators
    TNF Tumor necrosis factor
    TPL2 Serine/threonine kinase
    Vac Vacuum
    w/v Weight/volume
    w/w Weight/weight
    YPEG-rhIFNalpha-2a PEG-interferon alfa-2a
    YPEG-rhIFNalpha-2b Ypeginterferon alfa-2b
    δ Chemical shift (ppm)
    µg Microgram
    µL/ µl Microliter
    µM Micromolar
    µm Micrometer
    µmol Micromole
    • Example 1: N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-4-methyl-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0144
  • Methyl 3-formamido-4-methylbenzoate. A solution of methyl -3-amino-4-methylbenzoate (5.1 g, 31 mmol) in formic acid (42 mL) was stirred at 110 °C for 4 hr. The reaction mixture was allowed to cool to room temp. Water was added and the aqueous layer was washed three times with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated to give the desired product. C10H11NO3. 194.0 (M+1).
    Figure imgb0145
  • Methyl 3-formamido-4-methyl-2-nitrobenzoate. Methyl 3-formamido-4-methylbenzoate (5.3 g, 27 mmol) was added to fuming nitric acid at 0 °C portion wise over 45 min. The reaction mixture was stirred at 0 °C for an additional 1 h, and then ice was added and the mixture stirred for 1.5 h at room temperature. The precipitated solid was filtered, and washed with water. The solid was purified by silica gel to give the desired product. C10H10N2O5. 239.0 (M+1).
    Figure imgb0146
  • Methyl 4-methyl-1H-benzo[d]imidazole-7-carboxylate. A mixture of methyl 3-formamido-4-methyl-2-nitrobenzoate (1.0 g, 4.2 mmol) and iron (1.2 g, 21 mmol) in methanol (10 mL) and acetic acid (5 mL) was stirred at 70 °C for 3 hr. To the cooled reaction mixture was added ethyl acetate and water and the mixture was filtered and the solid was washed with ethyl acetate. The aqueous layer was washed two times with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated to give the desired product. C10H10N2O2. 191.1 (M+1).
    Figure imgb0147
  • N-(3-chloro-4-fluorophenyl)-4-methyl-1H-benzo[d]imidazole-7-carboxamide. To a solution of the 3-chloro-4-fluoroanilinein (253 mg, 1.74 mmol) dichloroethane at 0 °C under nitrogen was added trimethylaluminum (2 M in heptane, 1.74 mL, 3.47 mmol) dropwise over 5 min. The solution was allowed to warm to room temperature and stirred for 30 min. The solution was cooled to 0 °C and to this solution was added methyl 4-methyl-1H-benzo[d]imidazole-7-carboxylate (220 mg, 1.16 mmol). The solution was stirred at 85 °C for 6 hr and, then, cooled to room temperature. To the mixture was added ethyl acetate and 10% citric acid and the resulting precipitate was filtered and dried on high vac to give the desired product. C15H11ClFN3O. 304.4 (M+1).
    Figure imgb0148
  • N-(3-chloro-4-fluorophenyl)-N'-hydroxy-4-methyl-1H-benzo[d]imidazole-7-carboximidamide. A mixture of N-(3-chloro-4-fluorophenyl)-4-methyl-1H-benzo[d]imidazole-7-carboxamide (154 mg, 0.507 mmol), phosphorous pentachloride (158 mg, 0.761 mmol) in phosphoryl chloride (1.5 mL) and 1,2-dichloroethane (1.5 mL) were stirred at 80 °C for 2.5 hr. The reaction mixture was concentrated and suspended in ethanol (1.5 mL) and to this mixture was added 50% hydroxylamine in water (0.311 mL, 5.07 mmol). The reaction mixture stirred for 1 hr and was concentrated. The residue was purified by preparative HPLC to give the desired product. C15H12ClFN4O. 319.1 (M+1).
    • Example 2: N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-4-(trifluoromethoxy)-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0149
  • Nitric acid (18 mL) was cooled to -10 °C in a dry ice/acetone bath and methyl 2-formamido-4-(trifluoromethoxy)benzoate (1.97 g, 7.0 mol) was added and the reaction was allowed to stir for 4 hours at -10 °C. The reaction was slowly quenched with water (20 mL) and extracted with EtOAc (3x 10 mL). Combined organic layers were washed with brine (1 x 30 mL) and concentrated in vacuo to give methyl 2-formamido-3-nitro-4-(trifluoromethoxy)benzoate as a mixture of isomers.
  • Methyl 2-formamido-3-nitro-4-(trifluoromethoxy)benzoate (2.2 g, 7.0 mmol) was dissolved in ethanol (15 mL) and water (5 mL). Ammonium chloride (0.108 mol) was added in one portion and the reaction was allowed to stir at room temperature. Zinc powder (0.108 mol) was added portion-wise over 5 minutes and the reaction was allowed to stir 5 minutes after completion of addition. The zinc was then removed by vacuum filtration and the filtrate was concentrated in vacuo. The crude was dissolved in water (20 mL) and extracted with EtOAc (4 x 10 mL). Combined organic layers were washed with brine (1 x 50 mL), dried over sodium sulfate, and concentrated in vacuo to give methyl 3-amino-2-formamido-4-(trifluoromethoxy)benzoate.
  • Methyl 3-amino-2-formamido-4-(trifluoromethoxy)benzoate (1.32 g, 5.0 mmol) was dissolved in formic acid (15 mL) and heated to 80 °C for 1 hour. The reaction was cooled to rt, concentrated in vacuo, and quenched with saturated sodium bicarbonate solution (10 mL). The mixture was extracted with EtOAc (4x5 mL) and combined organic layers were washed with brine (1x15 mL) and concentrated in vacuo. Crude material was purified by column chromatography to give methyl 4-(trifluoromethoxy)-1H-benzo[d]imidazole-7-carboxylate.
    Figure imgb0150
  • N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-4-(trifluoromethoxy)-1H-benzo[d]imidazole-7-carboximidamide. Example 2 was made analogously to Example 10 using methyl 4-(trifluoromethoxy)-1H-benzo[d]imidazole-7-carboxylate in place of methyl 4,5-difluoro-1H-benzo[d]imidazole-7-carboxylate. C15H9ClF4N4O2. 389.0/391.1 (M+1).
    • Example 3: N-(3-Chloro-4-fluorophenyl)-6-fluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0151
  • Example 3 (N-(3-chloro-4-fluorophenyl)-6-fluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide) was made analogously to Example 59 using 6-fluoro-1H-benzo[d]imidazole-7-carboxylic acid in place of 1H-imidazo[4,5-b]pyridine-7-carboxylic acid. C14H9ClF2N4O. 323.1/325.0 (M+1).
    • Example 4: N-(3-Chloro-4-fluorophenyl)-5-fluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0152
  • Example 4 was made analogously to Example 59 using 5-fluoro-1H-benzo[d]imidazole-7-carboxylic in place of 1H-imidazo[4,5-b]pyridine-7-carboxylic acid. C14H9ClF2N4O. 323.1 (M+1). 1H NMR (400 MHz, DMSO-d 6) δ 11.01 (s, 1H), 8.87 (d, J = 15.9 Hz, 2H), 7.60 (dd, J = 8.7, 2.4 Hz, 1H), 7.20 (dd, J = 10.2, 2.4 Hz, 1H), 7.02 (t, J = 9.1 Hz, 1H), 6.95 (dd, J = 6.6, 2.7 Hz, 1H), 6.52 (ddd, J = 9.0, 4.1, 2.7 Hz, 1H).
    • Example 5: N-(3-Chloro-4-fluorophenyl)-4-fluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0153
  • Example 5 was made analogously to Example 59 using 4-fluoro-1H-benzo[d]imidazole-7-carboxylic acid in place of 1H-imidazo[4,5-b]pyridine-7-carboxylic acid. C14H9ClF2N4O. 323.1 (M+1). 1H NMR (400 MHz, DMSO-d6 ) δ 10.75 (s, 1H), 8.75 (s, 1H), 8.27 (s, 1H), 7.16 (dd, J = 8.4, 4.6 Hz, 1H), 7.09 - 6.94 (m, 2H), 6.90 (dd, J = 6.6, 2.7 Hz, 1H), 6.47 (ddd, J = 9.0, 4.0, 2.7 Hz, 1H).
    • Example 6: 4-Chloro-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0154
  • Example 6 was made analogously to Example 59 using 4-chloro-1H-benzo[d]imidazole-7-carboxylic acid in place of 1H-imidazo[4,5-b]pyridine-7-carboxylic acid. C14H9Cl2FN4O. 339.1 (M+1). 1H NMR (400 MHz, DMSO-d 6) δ 10.85 (s, 1H), 8.81 (s, 1H), 8.39 (s, 1H), 7.29 (d, J = 8.1 Hz, 1H), 7.18 (d, J = 8.1 Hz, 1H), 7.01 (t, J = 9.1 Hz, 1H), 6.93 (dd, J = 6.6, 2.7 Hz, 1H), 6.47 (ddd, J = 9.0, 4.0, 2.7 Hz, 1H).
    • Example 7: N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-4-(trifluoromethyl)-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0155
  • Example 7 was made analogously to Example 59 using 4-(trifluoromethyl)-1H-benzo[d]imidazole-7-carboxylic acid in place of 1H-imidazo[4,5-b]pyridine-7-carboxylic acid. C15H9ClF4N4O. 373.1 (M+1). 1H NMR (400 MHz, DMSO-d 6) δ 10.97 (d, J = 5.0 Hz, 1H), 8.83 (s, 1H), 8.35 (s, 1H), 7.52 (d, J = 7.9 Hz, 1H), 7.30 (d, J = 7.8 Hz, 1H), 7.01 (t, J = 9.1 Hz, 1H), 6.93 (dd, J = 6.6, 2.7 Hz, 1H), 6.46 (ddd, J = 9.0, 4.1, 2.8 Hz, 1H).
    • Example 8: N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0156
  • Example 8 was made analogously to Example 59 using 1H-benzo[d]imidazole-7-carboxylic acid in place of 1H-imidazo[4,5-b]pyridine-7-carboxylic acid. C14H10ClFN4O. 305.1 (M+1).
    • Example 9: N-(3-Chloro-4-fluorophenyl)-6-fluoro-N'-hydroxy-7-methyl-3H-benzimidazole-4-carboximidamide
  • Figure imgb0157
  • 3,5-difluoro-4-methyl-2-nitrobenzoic acid. To a solution of concentrated nitric acid (65% in water, 7.5 mL) and sulfuric acid (15 mL) at 0 °C was added 3,5-difluoro-4-methylbenzoic acid (5.0 g, 29 mmol) in portions over 1 hr. The solution was allowed to warm to room temperature and stirred for 18 hr. The reaction mixture was poured onto ice and the resulting precipitate was filtered and dried on high vac to give the desired product (6.3 g). C8H5F2NO4. 217.9 (M+1).
    Figure imgb0158
  • N-(3-chloro-4-fluorophenyl)-3,5-difluoro-4-methyl-2-nitrobenzamide. To a solution of 3-chloro-4-fluoroaniline (670 mg, 4.6 mmol), 3,5-difluoro-4-methyl-2-nitrobenzoic acid (1.0 g, 4.6 mmol), and triethylamine (1.9 mL, 14 mmol) in dichlromethane (40 mL) at 0 °C was added phosphoryl chloride (0.64 mL, 6.9 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 1 hr. To the reaction mixture was added saturated sodium bicarbonate and the aqueous layer was washed three times with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered, adsorbed onto silica and purified by silica gel chromatography to give the desired product (1.6 g). C14H8ClF3N2O3. 345.0 (M+1).
    Figure imgb0159
  • 3-amino-N-(3-chloro-4-fluorophenyl)-5-fluoro-4-methyl-2-nitrobenzamide. A solution of N-(3-chloro-4-fluorophenyl)-3,5-difluoro-4-methyl-2-nitrobenzamide (674 mg, 1.96 mmol) and 28% aqueous ammonium hydroxide in ethanol (2 mL) was stirred at 80 °C for 18 hr. To this solution was added water and the resulting precipitate was filtered and dried on high vac to give the desired product (583 mg). C14H10ClF2N3O3. 364.0 (M+23).
    Figure imgb0160
  • N-(3-chloro-4-fluorophenyl)-5-fluoro-3-formamido-4-methyl-2-nitrobenzamide. A mixture of acetic anhydride (0.4 mL, 4.3 mmol) in formic acid (4 mL) was stirred for 5 min. To this solution was added 3-amino-N-(3-chloro-4-fluorophenyl)-5-fluoro-4-methyl-2-nitrobenzamide (583 mg, 1.7 mmol). The reaction mixture stirred for 2 hr and was poured onto cold water and the resulting precipitate was filtered and dried on high vac to give the desired product (562 mg). C15H10ClF2N3O4. 370.0 (M+1).
    Figure imgb0161
  • N-(3-chloro-4-fluorophenyl)-5-fluoro-4-methyl-1H-benzo[d]imidazole-7-carboxamide was made analogously to Example 1 using N-(3-chloro-4-fluorophenyl)-5-fluoro-3-formamido-4-methyl-2-nitrobenzamide in place of methyl 3-formamido-4-methyl-2-nitrobenzoate. C15H10ClF2N3O. 322.2 (M+1).
    Figure imgb0162
  • N-(3-Chloro-4-fluorophenyl)-6-fluoro-N'-hydroxy-7-methyl-3H-benzimidazole-4-carboximidamide was made analogously to Example 1 using N-(3-chloro-4-fluorophenyl)-5-fluoro-4-methyl-1H-benzo[d]imidazole-7-carboxamide in place of N-(3-chloro-4-fluorophenyl)-4-methyl-1H-benzo[d]imidazole-7-carboxamide. C15H11ClF2N4O. 337.0 (M+1). 1H NMR (400 MHz, DMSO-d6 ) δ 10.97 (s, 1H), 8.96 (s, 1H), 8.86 (s, 1H), 7.20-7.11 (m, 1H), 7.01 (t, J = 9.2 Hz, 1H), 6.97 (dd, J = 6.5, 2.6 Hz, 1H), 2.44 (d, J = 1.6 Hz, 3H).
    • Example 10: N-(3-Chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0163
  • 3-Amino-4,5-difluoro-2-nitrobenzoic acid (15g, 68.8 mmol) was dissolved in methanol (200 mL) and sulfuric acid (20 mL) was added dropwise to the solution over 5 minutes. A reflux condenser was attached and the reaction was heated to 71 °C overnight. The reaction was then cooled to room temperature and concentrated in vacuo to approximately 50 mL of solvent. The reaction was neutralized to pH=7 with saturated potassium carbonate and then extracted with EtOAc (5 x 40 mL). Combined organic layers were washed with brine (1 x 60 mL) and concentrated in vacuo to give methyl 3-amino-4,5-difluoro-2-nitrobenzoate as a yellow solid which was used without further purification.
  • 3-Amino-4,5-difluoro-2-nitrobenzoate (14.5 g, 62 mmol) was dissolved in ethanol (150 mL) and water (50 mL). Ammonium chloride (0.934 mol) was added in one portion and the reaction was allowed to stir at room temperature. Zinc powder (0.934 mol) was added portion-wise over 5 minutes and the reaction was allowed to stir 5 minutes after completion of addition. The zinc was then removed by vacuum filtration and the filtrate was concentrated in vacuo. The crude was dissolved in water (60 mL) and extracted with EtOAc (4 x 40 mL). Combined organic layers were washed with brine (1 x 50 mL), dried over sodium sulfate, and concentrated in vacuo to give methyl 2,3-diamino-4,5-difluorobenzoate as a brown powder.
    Figure imgb0164
  • Methyl 2,3-diamino-4,5-difluorobenzoate (60 mg, 0.30 mmol) was dissolved in formic acid (2 mL) and heated to 100 °C in a sealed tube for 10 minutes. The reaction was allowed to cool to room temperature and concentrated in vacuo. The residue was dissolved in sat. sodium bicarbonate (2 mL) and extracted with EtOAc (3 x 3 mL). Combined organic layers were washed with water (1 x 5 mL) and concentrated in vacuo to give methyl 4,5-difluoro-1H-benzo[d]imidazole-7-carboxylate as a brown solid which was used without further purification.
  • Methyl 4,5-difluoro-1H-benzo[d]imidazole-7-carboxylate (12 mg, 0.056 mmol) was dissolved in DCE (1 mL) under an inert atmosphere. Trimethylaluminum (0.085 mL, 2.0 M in toluene) was added dropwise to the reaction followed by 3-chloro-4-fluoroaniline (0.085 mmol). The reaction was allowed to stir at rt overnight under inert atmosphere. The reaction was quenched with sat. sodium bicarb (3 mL) and extracted with EtOAc (3 x 2mL). Combined organic layers were washed with water (1 x 4 mL) and concentrated in vacuo to give N-(3-chloro-4-fluorophenyl)-4,5-difluoro-1H-benzo[d]imidazole-7-carboxamide which was used directly in the next reaction. The crude material was dissolved in POCl3 (2 mL) and PCl5 (0.083 mmol) was added. The reaction was heated to 85 °C in a sealed tube for 12 hours. The reaction was allowed to cool to room temperature and concentrated in vacuo. The residue was dissolved in a premixed solution of ethanol (2 mL) and hydroxylamine (0.55 mmol, 50% in water) and the reaction was allowed to stir at room temperature for 5 minutes. The reaction was concentrated in vacuo and purified by reverse-phase HPLC to afford N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide as a white solid. C14H8ClF3N4O. 341.1/343.2 (M+1). 1H NMR (400 MHz, DMSO-d6 ) δ 10.87 (s, 1H), 8.77 (s, 1H), 8.28 (s, 1H), 7.25 (d, J = 5.5 Hz, 1H), 7.03 (t, J = 9.0 Hz, 1H), 6.96 (dd, J = 6.5, 2.8 Hz, 1H), 6.48 (d, J = 9.1 Hz, 1H).
    • Example 11: 6-Chloro-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-1H-benzo[d]imidazole-4-carboximidamide
  • Figure imgb0165
  • Methyl 5-chloro-3-formamido-2-nitrobenzoate was made analogously to Example 1 using methyl 3-amino-5-chloro-2-nitrobenzoate in place of methyl 3-amino-4-methylbenzoate. C9H7ClN2O5. 281.1 (M+23).
    Figure imgb0166
  • Methyl 6-chloro-1H-benzo[d]imidazole-4-carboxylate was made analogously to Example 1 using methyl 5-chloro-3-formamido-2-nitrobenzoate in place of methyl 3-formamido-4-methyl-2-nitrobenzoate. C9H7ClN2O2. 211.2 (M+1).
    Figure imgb0167
  • 6-chloro-N-(3-chloro-4-fluorophenyl)-1H-benzo[d]imidazole-4-carboxamide was made analogously to Example 1 using methyl 6-chloro-1H-benzo[d]imidazole-4-carboxylate in place of methyl 4-methyl-1H-benzo[d]imidazole-7-carboxylate. C14H8Cl2FN3O. 324.2 (M+1).
    Figure imgb0168
  • 6-chloro-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-1H-benzo[d]imidazole-4-carboximidamide was made analogously to Example 1 using 6-chloro-N-(3-chloro-4-fluorophenyl)-1H-benzo[d]imidazole-4-carboxamide in place of N-(3-chloro-4-fluorophenyl)-4-methyl-1H-benzo[d]imidazole-7-carboxamide. C14H9Cl2FN4O. 339.0 (M+1).
    • Example 12: 4-Bromo-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0169
  • Methyl 4-bromo-3-formamidobenzoate was prepared analogously to Example 9, using methyl 3-amino-4-bromobenzoate in place of 3-amino-N-(3-chloro-4-fluorophenyl)-5-fluoro-4-methyl-2-nitrobenzamide. C9H8BrNO3. 279.9/281.9 [M+23]+.
    Figure imgb0170
  • Methyl 4-bromo-3-formamido-2-nitrobenzoate. To fuming nitric acid (14 mL) at -10 °C was added methyl 4-bromo-3-formamidobenzoate (5.1 g, 20 mmol), portionwise over 90 min. The mixture was stirred at 0 °C for 1 h and then poured over ice and allowed to stir and warm to rt over 1.5 h. The solid was isolated via filtration and the filter pad was washed with water. The solid was taken up in EtOAc, washed with brine, concentrated onto silica gel, and purified via column chromatography on silica gel to yield a mixture of the desired product and its regioisomer (3.5 g). C9H7BrN2O5. 324.9/326.9 [M+23]+.
    Figure imgb0171
  • Methyl 4-bromo-1H-benzo[d]imidazole-7-carboxylate was prepared analogously to Example 1, using methyl 4-bromo-3-formamido-2-nitrobenzoate in place of methyl 3-formamido-4-methyl-2-nitrobenzoate. C9H7BrN2O2. 254.9/256.9 [M+1]+.
    Figure imgb0172
  • 4-bromo-N-(3-chloro-4-fluorophenyl)-1H-benzo[d]imidazole-7-carboxamide was prepared analogously to Example 1 , using methyl 4-bromo-1H-benzo[d]imidazole-7-carboxylate in place of methyl 4-methyl-1H-benzo[d]imidazole-7-carboxylate. C14H8BrClFN3O. 368.0/369.9 [M+1]+.
    Figure imgb0173
  • 4-bromo-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide was prepared analogously to Example 1, using 4-bromo-N-(3-chloro-4-fluorophenyl)-1H-benzo[d]imidazole-7-carboxamide in place of N-(3-chloro-4-fluorophenyl)-4-methyl-1H-benzo[d]imidazole-7-carboxamide. C14H9BrClFN4O. 382.9/384.9 [M+1]+.
    • Example 13: 2-Amino-N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0174
  • Methyl 2,3-diamino-4,5-difluorobenzoate (0.5 g, 2.0 mmol) was dissolved in methanol (7.0 mL) and water (2.50 mL). Cyanogen bromide (3.0 mmol) was added and the reaction was refluxed in a sealed tube for 45 mins. The reaction was allowed to cool to rt and diluted with water (4 mL) and EtOAc (4 mL). The water layer was isolated and neutralized to pH=8 with sat. sodium carbonate. The neutralized aqueous layer was extracted with EtOAc (3x4 mL) and combined organic layers were washed with brine (1x5 mL), dried over sodium sulfate, and concentrated in vacuo to give methyl 2-amino-4,5-difluoro-1H-benzo[d]imidazole-7-carboxylate as a brown solid.
    Figure imgb0175
  • Methyl 2-amino-4,5-difluoro-1H-benzo[d]imidazole-7-carboxylate (75 mg, 0.33 mmol) was dissolved in DCE (4 mL) under inert atmosphere and cooled to 0 °C. Trimethylaluminium (1.2 mL, 2M hexanes) was added dropwise followed by 3-chloro-4-fluoroaniline (1.0 mmol) and the reaction was then heated to 70 °C for 2 days. The reaction was cooled to rt and quenched with saturated bicarbonate solution. The reaction was extracted with EtOAc (3x3 mL) and combined organic layers were washed with brine (1x6 mL) and concentrated in vacuo. The crude material was dried loaded on to silica gel and purified by column chromatography (EtOAc/hex) to give 2-amino-N-(3-chloro-4-fluorophenyl)-4,5-difluoro-1H-benzo[d]imidazole-7-carboxamide as a white powder.
  • 2-Amino-N-(3-chloro-4-fluorophenyl)-4,5-difluoro-1H-benzo[d]imidazole-7-carboxamide (20 mg, 0.0587 mmol) and Lawesson's reagent (0.176 mmol) was dissolved in toluene (2mL) and heated to 90°C overnight. The reaction was allowed to cool to rt and precipitates were removed by vacuum filtration and the filtrate was concentrated. The crude material was purified by column chromatography (EtOAc/hex) to give 2-amino-N-(3-chloro-4-fluorophenyl)-4,5-difluoro-1H-benzo[d]imidazole-7-carbothioamide as a yellow oil.
  • 2-Amino-N-(3-chloro-4-fluorophenyl)-4,5-difluoro-1H-benzo[d]imidazole-7-carbothioamide (20 mg, 0.0561 mmol) was dissolved in ethanol (2 mL) and hydroxylamine (50% in aqueous solution, 0.561 mmol) was added and the reaction was allowed to stir overnight at rt. The reaction was concentrated in vacuo and purified by reverse-phase HPLC to give 2-amino-N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide as a white solid. C14H9ClF3N5O. 356.0/357.9 (M+1). 1H NMR (400 MHz, Methanol-d 4) δ 7.27 (dd, J = 5.8, 2.7 Hz, 1H), 7.15 (t, J = 8.6 Hz, 1H), 7.03 - 6.98 (m, 2H), 6.94 (s, 1H), 6.67 (d, J = 3.8 Hz, 1H).
    • Example 14: 2-Amino-N-(3-bromo-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0176
  • Example 14 was made analogously to Example 13 using 3-bromo-4-fluoroaniline in place of 3-chloro-4-fluoroaniline. C14H9BrF3N5O. 400.0/402.0 (M+1). 1H NMR (400 MHz, DMSO-d6 ) δ 10.94 (s, 1H), 8.76 (s, 1H), 7.12 (dd, J = 6.1, 2.6 Hz, 1H), 7.06 (t, J = 8.8 Hz, 2H), 6.61 - 6.51 (m, 1H).
    • Example 15: 2-Amino-N-(3-bromophenyl)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0177
  • Example 15 was made analogously to Example 13 using 3-bromoaniline in place of 3-chloro-4-fluoroaniline. C12H10BrF2N5O. 382.0/384.1 (M+1). 1H NMR (400 MHz, Methanol-d 4) δ 7.11 - 6.96 (m, 4H), 6.69 - 6.63 (m, 1H).
    • Example 16: 2-Amino-N-(3-chlorophenyl)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0178
  • Example 16 was made analogously to Example 13 using 3-chloroaniline in place of 3-chloro-4-fluoroaniline. C14H10ClF2N5O. 338.0/340.1 (M+1). 1H NMR (400 MHz, Methanol-d 4) δ 8.69 - 8.59 (m, 2H), 8.51 - 8.45 (m, 1H), 8.39 (t, J = 2.1 Hz, 1H), 8.21 - 8.15 (m, 1H).
    • Example 17: 2-Amino-4,5-difluoro-N-(4-fluoro-3-(trifluoromethyl)phenyl)-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0179
  • Example 17 was made analogously to Example 13 using 4-fluoro-3-(trifluoromethyl)aniline in place of 3-chloro-4-fluoroaniline. C15H9F6N5O. 390.1 (M+1). 1H NMR (400 MHz, DMSO-d 6) δ 11.04 (s, 1H), 8.93 (s, 1H), 8.16 (s, 2H), 7.24 - 7.10 (m, 3H), 6.83 (dt, J = 7.9, 3.5 Hz, 1H).
    • Example 18: 2-Amino-N-(3-bromophenyl)-4-fluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0180
  • Example 18 was made analogously to Example 15 using methyl 2-amino-4-fluoro-1H-benzo[d]imidazole-7-carboxylate in place of 2-amino-4,5-difluoro-1H-benzo[d]imidazole-7-carboxylate. C14H11BrFN5O. 364.0/366.0 (M+1). 1H NMR (400 MHz, Methanol-d 4) δ 7.16 (dd, J = 8.8, 4.5 Hz, 1H), 7.09 - 6.92 (m, 4H), 6.65 (d, J = 8.1 Hz, 1H).
    • Example 19: 2-Amino-N-(3-bromo-4-fluorophenyl)-4-fluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0181
  • Example 19 was made analogously to Example 14 using methyl 2-amino-4-fluoro-1H-benzo[d]imidazole-7-carboxylate in place of 2-amino-4,5-difluoro-1H-benzo[d]imidazole-7-carboxylate. C14H10BrF2N5O. 382.0/384.0 (M+1). 1H NMR (400 MHz, Methanol-d 4) δ 7.15 (dd, J = 8.8, 4.6 Hz, 1H), 7.10 - 6.99 (m, 2H), 6.95 (t, J = 8.6 Hz, 1H), 6.69 (dt, J = 8.8, 3.5 Hz, 1H).
    • Example 20: 2-Amino-N-(3-chlorophenyl)-4-fluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0182
  • Example 20 was made analogously to Example 16 using methyl 2-amino-4-fluoro-1H-benzo[d]imidazole-7-carboxylate in place of 2-amino-4,5-difluoro-1H-benzo[d]imidazole-7-carboxylate. C14H11ClFN5O. 320.1/322.1 (M+1). 1H NMR (400 MHz, Methanol-d 4) δ 7.16 (dd, J = 8.8, 4.6 Hz, 1H), 7.10 - 6.99 (m, 2H), 6.89 (ddd, J = 8.0, 2.0, 0.9 Hz, 1H), 6.79 (t, J = 2.0 Hz, 1H), 6.64 - 6.58 (m, 1H).
    • Example 21: 2-Amino-4-fluoro-N-(4-fluoro-3-(trifluoromethyl)phenyl)-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0183
  • Example 21 was made analogously to Example 17 using methyl 2-amino-4-fluoro-1H-benzo[d]imidazole-7-carboxylate in place of 2-amino-4,5-difluoro-1H-benzo[d]imidazole-7-carboxylate. C15H10F5N5O. 372.1 (M+1). 1H NMR (400 MHz, DMSO-d6 ) δ 10.95 (s, 1H), 8.93 (s, 1H), 8.32 (s, 2H), 7.24 - 7.05 (m, 4H), 6.83 (dd, J = 8.5, 4.2 Hz, 1H).
    • Example 22: 2-Amino-N-(3-chloro-4-fluorophenyl)-4-fluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0184
  • 3-Amino-4-fluoro-2-nitrobenzoic acid (5g, 25 mmol) was dissolved in methanol (120 mL) and sulfuric acid (2.5 mL) was added dropwise to the solution over 5 minutes. A reflux condenser was attached and the reaction was heated to 71 °C overnight. The reaction was then cooled to room temperature and concentrated in vacuo to approximately 50 mL of solvent. The reaction was neutralized to pH=7 with saturated potassium carbonate and then extracted with EtOAc (5 x 40 mL). Combined organic layers were washed with brine (1 x 60 mL) and concentrated in vacuo to give methyl 3-amino-4-fluoro-2-nitrobenzoate as a yellow solid which was used without further purification.
  • 3-Amino-4-fluoro-2-nitrobenzoate (2.32 g, 11.0 mmol) was dissolved in ethanol (100 mL) and water (35 mL). Ammonium chloride (0.163 mol) was added in one portion and the reaction was allowed to stir at room temperature. Zinc powder (0.163 mol) was added portion-wise over 5 minutes and the reaction was allowed to stir 5 minutes after completion of addition. The zinc was then removed by vacuum filtration and the filtrate was concentrated in vacuo. The crude was dissolved in water (20 mL) and extracted with EtOAc (4 x 10 mL). Combined organic layers were washed with brine (1 x 50 mL), dried over sodium sulfate, and concentrated in vacuo to give methyl 2,3-diamino-4-fluorobenzoate as a brown powder.
    Figure imgb0185
  • Methyl 2,3-diamino-4-fluorobenzoate (0.1g, 0.54 mmol) was dissolved in methanol (2.0 mL) and water (1.0 mL). Cyanogen bromide (0.54 mmol) was added and the reaction was refluxed in a sealed tube for 45 mins. The reaction was allowed to cool to rt and diluted with water (4 mL) and EtOAc (4 mL). The water layer was isolated and neutralized to pH=8 with sat. sodium carbonate. The neutralized aqueous layer was extracted with EtOAc (3x4 mL) and combined organic layers were washed with brine (1x5 mL), dried over sodium sulfate, and concentrated in vacuo to give methyl 2-amino-4-fluoro-1H-benzo[d]imidazole-7-carboxylate as a brown solid.
    Figure imgb0186
  • Example 22 was made analogously to Example 13 (using methyl 2-amino-4-fluoro-1H-benzo[d]imidazole-7-carboxylate in place of 2-amino-4,5-difluoro-1H-benzo[d]imidazole-7-carboxylate. C14H10ClF2N5O. 338.1/339.2 (M+1). 1H NMR (400 MHz, Methanol-d 4) δ 7.14 (dd, J = 8.8, 4.6 Hz, 1H), 7.00 (dt, J = 23.9, 9.2 Hz, 2H), 6.91 (dd, J = 6.4, 2.7 Hz, 1H), 6.64 (dt, J = 8.8, 3.4 Hz, 1H).
    • Example 23: N-(3-Chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((2-morpholinoethyl)amino)-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0187
  • Methyl 4,5-difluoro-2-((2-morpholinoethyl)amino)-1H-benzo[d]imidazole-7-carboxylate. Dissolved methyl 2,3-diamino-4,5-difluorobenzoate (50 mg, 0.25 mmol) in THF (3 ml), to the solution was added 4-(2-isothiocyanatoethyl)morpholine (0.43 g, 0.002 mmol) and triethylamine (0.36 g, 0.003 mol). The reaction mixture was heated at 80°C overnight, then to the reaction mixture was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.47 g, 0.002 mol), heated at 80°C for 1h. The reaction mixture was diluted with EtOAc, and washed with NaHCO3 saturated solution, organic layer was evaporated and the residue was purified with Combi-Flash column chromatography to afford 84mg desired product. C15H18F2N4O3. 341.2 (M+1).
    Figure imgb0188
  • N-(3-chloro-4-fluorophenyl)-4,5-difluoro-2-((2-morpholinoethyl)amino)-1H-benzo[d]imidazole-7-carboxamide. Dissolved 3-chloro-4-fluoroaniline (12.8mg, 0.088 mmol) in dichloroethane (2 ml), to the solution was added trimethylamine (0.088 ml, 2M in toluene) and triethylamine (0.36 g, 0.003 mol). Then to the raction mixture was added methyl 4,5-difluoro-2-((2-morpholinoethyl)amino)-1H-benzo[d]imidazole-7-carboxylate (20 mg, 0.06 mmol). The reaction mixture was stirred at room temperature for 2h, then the reaction mixture was diluted with EtOAc, and washed with NaHCO3 saturated solution, organic layer was evaporated and the residue was purified with Combi-Flash column chromatography to afford 27mg desired product. C20H19ClF3N5O2. 454.4 (M+1).
    Figure imgb0189
  • N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((2-morpholinoethyl)amino)-1H-benzo[d]imidazole-7-carboximidamide. Example 23 was made analogously to Example 107 using the general procedure for hydroxy amidine formation. C20H20ClF3N6O2. 469.1 (M+1). 1H NMR (400 MHz, Methanol-d4) δ 7.01 - 6.85 (m, 3H), 6.67 (ddd, J = 8.9, 4.0, 2.8 Hz, 1H), 4.00 (t, J = 4.8 Hz, 4H), 3.81 - 3.73 (m, 2H), 3.49 - 3.36 (m, 6H).
    • Example 24: N-(3-Chlorophenyl)-4,5-difluoro-N'-hydroxy-2-(((3-methoxypropyl)amino)methyl)-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0190
  • N-(3-chlorophenyl)-4,5-difluoro-2-(methoxymethyl)-1H-benzo[d]imidazole-7-carboxamide was prepared analogously to Example 45, using 3-chloroaniline in place of 3-chloro-4-fluoroaniline. C16H12ClN3O2. 352.1 [M+1]+.
    Figure imgb0191
  • 4-(3-chlorophenyl)-3-(4,5-difluoro-2-(methoxymethyl)-1H-benzo[d]imidazol-7-yl)-1,2,4-oxadiazol-5(4H)-one was prepared analogously to Example 45, using N-(3-chlorophenyl)-4,5-difluoro-2-(methoxymethyl)-1H-benzo[d]imidazole-7-carboxamide in place of N-(3-chloro-4-fluorophenyl)-4,5-difluoro-2-(methoxymethyl)-1H-benzo[d]imidazole-7-carboxamide. C17H11ClF2N4O3. 393.0 [M+1]+.
    Figure imgb0192
  • 3-(2-(bromomethyl)-4,5-difluoro-1H-benzo[d]imidazol-7-yl)-4-(3-chlorophenyl)-1,2,4-oxadiazol-5(4H)-one and 4-(3-chlorophenyl)-3-(4,5-difluoro-2-(hydroxymethyl)-1H-benzo[d]imidazol-7-yl)-1,2,4-oxadiazol-5(4H)-one were prepared analogously to Example 45, using 4-(3-chlorophenyl)-3-(4,5-difluoro-2-(methoxymethyl)-1H-benzo[d]imidazol-7-yl)-1,2,4-oxadiazol-5(4H)-one in place of 4-(3-chloro-4-fluorophenyl)-3-(4,5-difluoro-2-(methoxymethyl)-1H-benzo[d]imidazol-7-yl)-1,2,4-oxadiazol-5(4H)-one. C16H8BrClF2N4O2. 440.9/442.9 [M+1]+. C16H9ClF2N4O3. 379.0 [M+1]+.
    Figure imgb0193
  • N-(3-chlorophenyl)-4,5-difluoro-N'-hydroxy-2-(((3-methoxypropyl)amino)methyl)-1H-benzo[d]imidazole-7-carboximidamide. Example 24 was prepared analogously to Example 45, using 3-(2-(bromomethyl)-4,5-difluoro-1H-benzo[d]midazol-7-yl)-4-(3-chlorophenyl)-1,2,4-oxadiazol-5(4H)-one in place of 3-(2-(bromomethyl)-4,5-difluoro-1H-benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one. C19H20ClF2N5O2. 424.1 [M+1]+.
    • Example 25: N-(3-Chlorophenyl)-2-(((cyclopropylmethyl)amino)methyl)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0194
  • Example 25 was prepared analogously to Example 45 , using 3-(2-(bromomethyl)-4,5-difluoro-1H-benzo[d]imidazol-7-yl)-4-(3-chlorophenyl)-1,2,4-oxadiazol-5(4H)-one and cyclopropylmethanamine in place of 3-(2-(bromomethyl)-4,5-difluoro-1H-benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one and 3-methoxypropylamine, respectively. C19H18ClF2N5O. 406.1 [M+1]+.
    • Example 26: N-(3-Chlorophenyl)-2-((dimethylamino)methyl)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0195
  • Example 26 was prepared analogously to Example 45, using 3-(2-(bromomethyl)-4,5-difluoro-1H-benzo[d]imidazol-7-yl)-4-(3-chlorophenyl)-1,2,4-oxadiazol-5(4H)-one and dimethylamine in place of 3-(2-(bromomethyl)-4,5-difluoro-1H-benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one and 3-methoxypropylamine, respectively. C17H16ClF2N5O. 380.1 [M+1]+. 1H NMR (400 MHz, DMSO-d6 ) δ 12.93 (br s, 1H), 11.00 (br s, 1H), 10.27 (br s, 1H), 8.86 (s, 1H), 7.38 - 7.23 (m, 1H), 7.06 - 6.96 (m, 1H), 6.85 (t, J = 2.1 Hz, 1H), 6.81 (d, J = 7.8 Hz, 1H), 6.47 (dd, J = 8.2, 1.8 Hz, 1H), 4.58 (s, 2H), 2.85 (s, 6H).
    • Example 27: N-(3-Chlorophenyl)-4,5-difluoro-N'-hydroxy-2-((isopropylamino)methyl)-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0196
  • Example 27 was prepared analogously to Example 45, using 3-(2-(bromomethyl)-4,5-difluoro-1H-benzo[d]imidazol-7-yl)-4-(3-chlorophenyl)-1,2,4-oxadiazol-5(4H)-one and isopropylamine in place of 3-(2-(bromomethyl)-4,5-difluoro-1H-benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one and 3-methoxypropylamine, respectively. C18H18ClF2N5O. 394.1 [M+1]+. 1H NMR (400 MHz, DMSO-d6 ) δ 12.88 (br s, 1H), 11.03 (br s, 1H), 9.27 (br s, 3H), 8.85 (s, 1H), 7.31 - 7.20 (m, 1H), 7.04 (t, J = 8.1 Hz, 1H), 6.83 (d, J = 8.1 Hz, 1H), 6.80 (t, J = 2.1 Hz, 1H), 6.49 (dd, J = 8.3, 1.8 Hz, 1H), 4.51 - 4.43 (m, 2H), 3.54 - 3.35 (m, 1H), 1.28 (d, J = 6.3 Hz, 6H).
    • Example 28: N-(3-Chlorophenyl)-2-((ethylamino)methyl)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0197
  • Example 28 was prepared analogously to Example 45, using 3-(2-(bromomethyl)-4,5-difluoro-1H-benzo[d]imidazol-7-yl)-4-(3-chlorophenyl)-1,2,4-oxadiazol-5(4H)-one and ethylamine in place of 3-(2-(bromomethyl)-4,5-difluoro-1H-benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one and 3-methoxypropylamine, respectively. C17H16ClF2N5O. 380.1 [M+1]+. 1H NMR (400 MHz, DMSO-d6 ) δ 12.87 (br s, 1H), 11.01 (br s, 1H), 9.27 (br s, 2H), 8.85 (s, 1H), 7.30 - 7.21 (m, 1H), 7.03 (t, J = 8.0 Hz, 1H), 6.87 - 6.78 (m, 2H), 6.52 - 6.45 (m, 1H), 4.54 - 4.38 (m, 2H), 3.17 - 2.98 (m, 2H), 1.23 (t, J = 7.2 Hz, 3H).
    • Example 29: N-(3-Chlorophenyl)-4,5-difluoro-N'-hydroxy-2-(hydroxymethyl)-1H-benzo[d]olimidazole-7-carboximidamide
  • Figure imgb0198
  • Example 29 was prepared analogously to Example 46, using 4-(3-chlorophenyl)-3-(4,5-difluoro-2-(hydroxymethyl)-1H-benzo[d]imidazol-7-yl)-1,2,4-oxadiazol-5(4H)-one in place of 4-(3-chloro-4-fluorophenyl)-3-(4,5-difluoro-2-(hydroxymethyl)-1H-benzo[d]imidazol-7-yl)-1,2,4-oxadiazol-5(4H)-one. C15H11ClF2N4O2. 353.0 [M+1]+. 1H NMR (400 MHz, DMSO-d6 ) δ 11.00 (br s, 1H), 8.79 (s, 1H), 7.16 (dd, J = 12.0, 7.0 Hz, 1H), 7.07 - 7.00 (m, 1H), 6.85 - 6.79 (m, 2H), 6.53 - 6.47 (m, 1H), 4.67 (s, 2H).
    • Example 30: N-(3-Chlorophenyl)-4,5-difluoro-N'-hydroxy-2-((methylamino)methyl)-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0199
  • Example 30 was prepared analogously to Example 45, using 3-(2-(bromomethyl)-4,5-difluoro-1H-benzo[d]imidazol-7-yl)-4-(3-chlorophenyl)-1,2,4-oxadiazol-5(4H)-one and methylamine in place of 3-(2-(bromomethyl)-4,5-difluoro-1H-benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one and 3-methoxypropylamine, respectively. C16H14ClF2N5O. 366.0 [M+1]+. 1H NMR (400 MHz, DMSO-d6 ) δ 12.86 (br s, 1H), 11.00 (br s, 1H), 9.24 (br s, 2H), 8.84 (s, 1H), 7.30 - 7.19 (m, 1H), 7.03 (t, J = 8.0 Hz, 1H), 6.88 - 6.75 (m, 2H), 6.53 - 6.45 (m, 1H), 4.45 (t, J = 5.6 Hz, 2H), 2.74 - 2.64 (m, 3H).
    • Example 31: 2-(Aminomethyl)-N-(3-chlorophenyl)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0200
  • Example 31 was prepared analogously to Example 45, using 3-(2-(bromomethyl)-4,5-difluoro-1H-benzo[d]imidazol-7-yl)-4-(3-chlorophenyl)-1,2,4-oxadiazol-5(4H)-one and ammonia (0.5 M solution in dioxane) in place of 3-(2-(bromomethyl)-4,5-difluoro-1H-benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one and 3-methoxypropylamine, respectively. C15H12ClF2N5O. 352.0 [M+1]+ 1H NMR (400 MHz, DMSO-d6 ) δ 12.77 (br s, 1H), 11.00 (br s, 1H), 8.83 (s, 1H), 8.52 (br s, 3H), 7.21 (dd, J = 12.0, 6.9 Hz, 1H), 7.04 (t, J = 8.1 Hz, 1H), 6.83 (dd, J = 7.8, 2.0 Hz, 1H), 6.80 (t, J = 2.1 Hz, 1H), 6.49 (dd, J = 8.2, 2.1 Hz, 1H), 4.34 (q, J = 5.4 Hz, 2H).
    • Example 32: N-(3-Chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-morpholino-1H-benzo-[d]imidazole-7-carboximidamide
  • Figure imgb0201
  • Methyl 2,3-diamino-4,5-difluorobenzoate (5.0 g, 25 mmol, 1 equiv) was dissolved in formic acid (120 mL) and stirred at 80 °C for 3 hours. Formic acid was subsequently removed in vacuo and methyl 4,5-difluoro-1H-benzo[d]imidazole-7-carboxylate was obtained as a brown solid. C9H6F2N2O2, 213.0 (M+1). 1H NMR (400 MHz, DMSO-d 6) δ 8.43 (s, 1H), 7.83 (dd, J = 11.5, 7.2 Hz, 1H), 3.95 (s, 3H). 19F NMR (377 MHz, DMSO-d 6) δ -146.16 (dd, J = 21.8, 7.2 Hz, 1F), -149.09 (dd, J = 21.8, 11.6 Hz, IF).
  • To a suspension of methyl 4,5-difluoro-1H-benzo[d]imidazole-7-carboxylate (6.0 g, 28 mmol, 1 equiv) in THF (60 mL) was added a 60 wt% dispersion of NaH (1.7 g, 42 mmol, 1.5 equiv) in three portions. Once gas evolution ceased, the reaction mixture was cooled to 0 °C and SEM-Cl (6.0 mL, 34 mmol, 1.2 equiv) was added. The ice bath was subsequently removed and the reaction was stirred at room temperature for 3 hours before being quenched with saturated aqueous NH4Cl. The reaction mixture was diluted with water and extracted three times with EtOAc. The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (0-5% MeOH/CH2Cl2 over 20 minutes). Methyl 4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-7-carboxylate was isolated as a yellow solid. C15H20F2N2O3Si, 342.9 (M+1). 1H NMR (400 MHz, Chloroform-d) δ 8.17 (s, 1H), 7.91 (dd, J = 11.5, 7.5 Hz, 1H), 5.68 (s, 2H), 4.06 (s, 3H), 3.64 - 3.45 (m, 2H), 0.98 - 0.85 (m, 2H), -0.04 (d, J = 0.6 Hz, 9H). 19F NMR (377 MHz, Chloroform-d) δ -144.34 (m, 1F), -150.20 (m, 1F).
    Figure imgb0202
  • To a solution of methyl 4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-7-carboxylate (2.2 g, 6 mmol, 1 equiv) in acetonitrile (46.2 mL) was added NCS (1.29 g, 10 mmol, 1.5 equiv). The reaction mixture was stirred at 100 °C in a sealed vessel for 12 hours. Acetonitrile was subsequently removed in vacuo and the crude product purified by silica gel chromatography (0-5% MeOH/CH2Cl2 over 20 minutes). Methyl 2-chloro-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-7-carboxylate was obtained as a crystalline yellow solid. C15H19ClF2N2O3Si, 376.9/378.9 (M+1).
    Figure imgb0203
  • To a solution of Methyl 2-chloro-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-7-carboxylate (0.29 g, 0.46 mmol, 1 equiv) in DMSO (2 mL) was added morpholine (0.14 mL, 1.6 mmol, 3.5 equiv). The reaction was stirred at 60 °C for 3 hours before being diluted with DMF/H2O and purified by reverse phase HPLC (10-90% CH3CN/H2O over 20 mins). The TFA salt of methyl 4,5-difluoro-2-morpholino-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-7-carboxylate was obtained as a white solid. C19H27F2N3O4Si, 428.1 (M+1).
    Figure imgb0204
  • N-(3-Chloro-4-fluorophenyl)-4,5-difluoro-2-morpholino-1H-benzo[d]imidazole-7-carboxamide was made analogously to Example 13 using methyl 4,5-difluoro-2-morpholino-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-7-carboxylate and 3-chloro-4-fluoroaniline in place of methyl 2-amino-4,5-difluoro-1H-benzo[d]imidazole-7-carboxylate. C18H14ClF3N4O2, 411.1/413.0 (M+1).
    Figure imgb0205
  • Example 32 was made analogously to Example 59 using N-(3-chloro-4-fluorophenyl)-4,5-difluoro-2-morpholino-1H-benzo[d]imidazole-7-carboxamide in place of N-(3-chloro-4-fluorophenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide. C18H15ClF3N5O2. 426.1/428.1 (M+1). 1H NMR (400 MHz, DMSO-d6 ) δ 10.78 (br. s, 1H), 8.82 (s, 1H), 7.04 (t, J = 9.1 Hz, 1H), 7.00 (dd, J = 6.6, 2.7 Hz, 1H), 6.93 (dd, J = 12.1, 6.9 Hz, 1H), 6.51 (ddd, J = 9.0, 4.1, 2.7 Hz, 1H), 3.69 - 3.62 (m, 4H), 3.53 - 3.44 (m, 4H).
    • Example 33: N-(3-Chloro-4-fluorophenyl)-4-fluoro-N'-hydroxy-2-((2-(methylsulfonyl)ethyl)amino)-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0206
  • Methyl 2,3-diamino-4-fluorobenzoate (150 mg, 0.814 mmol) and 1-isothiocyanato-2-(methylsulfonyl)ethane (5.0 mmol) were dissolved in THF (4.5 mL) and triethylamine (7.0 mmol) was added and the reaction was heated to reflux overnight. 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (5.0 mmol) was added and the reaction was allowed to heat at reflux for an additional 1 hour. The reaction was allowed to cool to room temperature, quenched with water, and extracted with EtOAc (3x 3 mL). The combined organic layers were washed with brine (1x4mL), concentrated, and purified by silica gel column chromatography to give methyl 4-fluoro-2-((2-(methylsulfonyl)ethyl)amino)-1H-benzo[d]imidazole-7-carboxylate.
    Figure imgb0207
  • Example 33 was made analogously to Example 22 using methyl 4-fluoro-2-((2-(methylsulfoyl)ethyl)amino)-1H-benzo[d]imidazole-7-carboxylate in place of methyl 2-amino-4-fluoro-1H-benzo[d]imidazole-7-carboxylate. C17H16ClF2N5O3S. 444.1/446/1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 10.89 (s, 1H), 8.85 (s, 1H), 7.12 - 6.98 (m, 3H), 6.95 (dd, J = 6.5, 2.7 Hz, 1H), 6.55 (ddd, J = 9.0, 4.1, 2.7 Hz, 1H), 3.89 (d, J = 6.3 Hz, 2H), 3.51 (t, J = 6.1 Hz, 2H), 3.08 (s, 3H).
    • Example 34: N-(3-Chloro-4-fluorophenyl)-4-fluoro-N'-hydroxy-2-((2-morpholinoethyl)amino)-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0208
  • Example 34 was made analogously to Example 33 using 4-(2-isothiocyanatoethyl)morpholine in place of 1-isothiocyanato-2-(methylsulfonyl)ethane.
    • Example 35: N-(3-Chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((2-(methylsulfonyl)ethyl)amino)-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0209
  • Example 35 was made analogously to Example 39 using 2-(methylsulfonyl)ethanamine in place of N1,N1-dimethylpropane-1,3-diamine with an addition of triethylamine (1.2 eq) in the cyclization reaction. C17H15ClF3N5O3S. 462.1/464.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 8.82 (d, J = 4.0 Hz, 1H), 7.65 (s, 1H), 7.10 (t, J = 9.1 Hz, 1H), 7.03 - 6.91 (m, 2H), 6.55 (dt, J = 9.0, 3.5 Hz, 1H), 3.84 (d, J = 5.9 Hz, 2H), 3.48 (t, J = 6.4 Hz, 2H), 3.06 (s, 3H).
    • Example 36: N-(3-Chloro-4-fluorophenyl)-2-((2-(4,4-difluoropiperidin-1-yl)ethyl)amino)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0210
  • Example 36 was made analogously to Example 39 using 2-(4,4-difluoropiperidin-1-yl)ethanamine in place of N1,N1-dimethylpropane-1,3-diamine. C21H20ClF5N6O. 503.2/505/2 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 10.81 (s, 1H), 8.71 (s, 1H), 6.94 (dd, J = 6.5, 2.8 Hz, 1H), 6.87 (dd, J = 12.2, 6.9 Hz, 1H), 6.76 (s, 1H), 6.59 (s, 1H), 6.53 (ddd, J = 9.0, 4.1, 2.8 Hz, 1H), 3.78 - 3.67 (m, 2H), 3.50 (s, 4H), 3.41 (t, J = 5.7 Hz, 2H), 2.34 (dt, J = 13.6, 7.8 Hz, 4H).
    • Example 37: N-(3-Chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((1-morpholinopropan-2-yl)amino)-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0211
  • Example 37 was made analogously to Example 39 using 1-morpholinopropan-2-amine in place of N1,N1-dimethylpropane-1,3-diamine. C21H22ClF3N6O2. 483.1/485.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 10.82 (s, 1H), 8.69 (s, 1H), 7.14 - 6.97 (m, 2H), 6.93 (dd, J = 6.6, 2.8 Hz, 1H), 6.87 (dd, J = 12.3, 7.1 Hz, 1H), 6.58 - 6.49 (m, 1H), 4.41 - 4.26 (m, 1H), 3.85 (s, 4H), 3.49 (s, 2H), 3.32 (d, J = 6.3 Hz, 4H), 1.26 (d, J = 6.7 Hz, 3H).
    • Example 38: N-(3-Chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-(methylamino)-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0212
  • To a solution of methyl 2-chloro-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-7-carboxylate (0.16 g, 0.43 mmol, 1 equiv) in DMSO (1 mL) was added a 2 M solution of methylamine in methanol (0.76 mL, 1.51 mmol, 3.5 equiv) and triethylamine (0.06 mL, 0.43 mmol, 1 equiv). The reaction was stirred at 60 °C for 2 hours before being diluted with water and extracted with EtOAc. The combined organics were dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (0-3% MeOH/CH2Cl2). Methyl 4,5-difluoro-2-(methylamino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-7-carboxylate was obtained as a yellow oil. C16H23F2N3O3Si. 372.05 (M+1).
    Figure imgb0213
  • N-(3-Chloro-4-fluorophenyl)-4,5-difluoro-2-(methylamino)-1H-benzo[d]imidazole-7-carboxamide was made analogously to Example 13 using methyl 4,5-difluoro-2-(methylamino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-7-carboxylate and 3-chloro-4-fluoroaniline in place of methyl 2-amino-4,5-difluoro-1H-benzo[d]imidazole-7-carboxylate and stirring overnight at room temperature. The crude product was purified by reverse phase HPLC (10-90% CH3CN/H2O over 20 mins) and the TFA salt of N-(3-chloro-4-fluorophenyl)-4,5-difluoro-2-(methylamino)-1H-benzo[d]imidazole-7-carboxamide was isolated as a white solid. C15H10ClF3N4O. 355.06/356.98 (M+1).
    Figure imgb0214
  • Example 38 was made analogously to Example 59 using N-(3-chloro-4-fluorophenyl)-4,5-difluoro-2-(methylamino)-1H-benzo[d]imidazole-7-carboxamide in place of N-(3-chloro-4-fluorophenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide. The TFA salt of N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-(methylamino)-1H-benzo[d]imidazole-7-carboximidamide was isolated as a white solid. C15H11ClF3N5O. 370.05/371.98 (M+1). 1H NMR (400 MHz, DMSO-d 6) δ 10.94 (s, 1H), 8.79 (s, 1H), 7.08 (t, J = 9.0 Hz, 1H), 7.06 - 7.01 (m, 1H), 6.99 (dd, J = 6.6, 2.7 Hz, 1H), 6.53 (ddd, J = 8.9, 4.0, 2.7 Hz, 1H), 2.98 (d, J = 3.7 Hz, 3H). 19F NMR (377 MHz, DMSO-d 6) δ -73.7, - 126.8 , -147.4 , -155.1 (TFA salt).
    • Example 39: N-(3-Chloro-4-fluorophenyl)-2-((3-(dimethylamino)propyl)amino)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0215
  • To a solution of methyl 2-chloro-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-7-carboxylate (0.25 g, 0.66 mmol, 1 equiv) in DMSO (1.25 mL) was added N,N-dimethylpropane-1,3-diamine (0.10 mL, 0.81 mmol, 1.2 equiv). The reaction was stirred at 60 °C for 6 hours before being diluted with DMF/water and purified by reverse phase HPLC (10-90% CH3CN/H2O over 15 mins). The TFA salt of methyl 2-((3-(dimethylamino)propyl)amino)-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-7-carboxylate was obtained as a yellow oil. C20H32F2N4O3Si. 443.18 (M+1).
    Figure imgb0216
  • To a solution of methyl 2-((3-(dimethylamino)propyl)amino)-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-7-carboxylate (TFA salt, 159 mg, 0.36 mmol, 1 equiv) and 3-chloro-4-fluoroaniline (209 mg, 1 mmol, 4 equiv) in DCE (7.5 mL) was added a 2 M solution of AlMe3 in toluene (1.26 mL, 3 mmol, 7 equiv) at room temperature. The reaction was stirred overnight before quenching with 2 M aqueous NaOH and extracting with ethyl acetate. The combined organics were dried over MgSO4, filtered and concentrated in vacuo. The crude product was dissolved in CH2Cl2 (2 mL) and TFA (2 mL) was added. The SEM-deprotection was stirred overnight before being concentrated in vacuo. The crude product was purified by reverse phase HPLC (10-90% CH3CN/H2O over 15 mins). The TFA salt of N-(3-chloro-4-fluorophenyl)-2-((3-(dimethylamino)propyl)amino)-4,5-difluoro-1H-benzo[d]-imidazole-7-carboxamide was obtained as an off-white solid. C19H19ClF3N5O. 426.18/428.13 (M+1).
    Figure imgb0217
  • Example 39 was made analogously to Example 59 using N-(3-chloro-4-fluorophenyl)-2-((3-(dimethylamino)propyl)amino)-4,5-difluoro-1H-benzo[d]imidazole-7-carboxamide in place of N-(3-chloro-4-fluorophenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide. The TFA salt of N-(3-chloro-4-fluorophenyl)-2-((3-(dimethylamino)propyl)amino)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide was isolated as a white solid. C19H20ClF3N6O. 441.12/443.09 (M+1). 1H NMR (400 MHz, DMSO-d 6) δ 10.85 (s, 1H), 9.72 (s, 1H), 8.74 (s, 1H), 7.09 (t, J = 9.1 Hz, 1H), 7.00 - 6.85 (m, 2H), 6.55 (ddd, J = 9.0, 4.1, 2.7 Hz, 1H), 3.42 (m, 2H), 3.10 (m, 2H), 2.80 (s, 6H), 1.93 (m, 2H). 19F NMR (377 MHz, DMSO-d 6) δ -73.7, -127.1, - 149.4, -156.5.
    • Example 40: N-(3-Chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((2-methoxyethyl)amino)-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0218
  • Methyl 4,5-difluoro-2-((2-methoxyethyl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-7-carboxylate was made analogously to Example 39 using 2-methoxyethanamine and triethylamine (1 equiv) in place of N,N-dimethylpropane-1,3-diamine. The TFA salt of methyl 4,5-difluoro-2-((2-methoxyethyl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-7-carboxylate was isolated as a yellow oil. C18H27F2N3O4Si. 416.09/417.07 (M+1).
    Figure imgb0219
  • N-(3-chloro-4-fluorophenyl)-4,5-difluoro-2-((2-methoxyethyl)amino)-1H-benzo[d]imidazole-7-carboxamide was made analogously to Example 39 using methyl 4,5-difluoro-2-((2-methoxyethyl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-7-carboxylate in place of methyl 2-((3-(dimethylamino)propyl)amino)-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-7-carboxylate. The TFA salt of N-(3-chloro-4-fluorophenyl)-4,5-difluoro-2-((2-methoxyethyl)amino)-1H-benzo[d]imidazole-7-carboxamide was isolated as a white solid. C17H14ClF3N4O2. 399.09/401.02 (M+1).
    Figure imgb0220
  • Example 40 was made analogously to Example 59 using N-(3-chloro-4-fluorophenyl)-4,5-difluoro-2-((2-methoxyethyl)amino)-1H-benzo[d]imidazole-7-carboxamide in place of N-(3-chloro-4-fluorophenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide . The TFA salt of N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((2-methoxyethyl)amino)-1H-benzo[d]imidazole-7-carboximidamide was isolated as a white solid. C17H15ClF3N5O2. 414.09/416.01 (M+1). 1H NMR (400 MHz, DMSO-d 6) δ 10.98 (s, 1H), 8.79 (s, 1H), 8.11 (s, 1H), 7.09 (t, J = 9.1 Hz, 1H), 7.04 (dd, J = 12.1, 7.0 Hz, 1H), 6.99 (dd, J = 6.6, 2.7 Hz, 1H), 6.55 (ddd, J = 8.9, 4.0, 2.7 Hz, 1H), 3.56 (t, J = 5.1 Hz, 2H), 3.51 (t, J = 4.7 Hz, 2H), 3.29 (s, 3H). 19F NMR (377 MHz, DMSO-d 6) δ - 75.18 (6F), -126.96 (1F), -147.44 (1F), -155.18 (1F).
    • Example 41: N-(3-Chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((2-(pyrrolidin-1-yl)ethyl)amino)-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0221
  • Methyl 4,5-difluoro-2-((2-(pyrrolidin-1-yl)ethyl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-7-carboxylate was made analogously to Example 39 using 2-(pyrrolidin-1-yl)ethanamine in place of N,N-dimethylpropane-1,3-diamine. The TFA salt of methyl 4,5-difluoro-2-((2-(pyrrolidin-1-yl)ethyl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-7-carboxylate was isolated as a yellow oil. C21H32F2N4O3Si. 455.21 (M+1).
    Figure imgb0222
  • N-(3-Chloro-4-fluorophenyl)-4,5-difluoro-2-((2-(pyrrolidin-1-yl)ethyl)amino)-1H-benzo[d]imidazole-7-carboxamide was made analogously to Example 39 using methyl 4,5-difluoro-2-((2-(pyrrolidin-1-yl)ethyl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-7-carboxylate in place of methyl 2-((3-(dimethylamino)propyl)amino)-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-7-carboxylate. The TFA salt of N-(3-chloro-4-fluorophenyl)-4,5-difluoro-2-((2-(pyrrolidin-1-yl)ethyl)amino)-1H-benzo[d]imidazole-7-carboxamide was isolated as a white solid. C20H19ClF3N5O. 438.21/440.12 (M+1).
    Figure imgb0223
  • Example 41 was made analogously to Example 59 using N-(3-chloro-4-fluorophenyl)-4,5-difluoro-2-((2-(pyrrolidin-1-yl)ethyl)amino)-1H-benzo[d]imidazole-7-carboxamide in place of N-(3-chloro-4-fluorophenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide. The TFA salt of N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((2-(pyrrolidin-1-yl)ethyl)amino)-1H-benzo[d]imidazole-7-carboximidamide was isolated as a white solid. C20H20ClF3N6O. 453.14/455.11 (M+1). 1H NMR (400 MHz, DMSO-d 6) δ 10.78 (s, 1H), 9.84 (s, 1H), 8.70 (s, 1H), 7.09 (t, J = 9.1 Hz, 1H), 7.02 (s, 1H), 6.93 (dd, J = 6.6, 2.7 Hz, 1H), 6.84 (dd, J = 12.3, 6.9 Hz, 1H), 6.53 (ddd, J = 9.0, 4.0, 2.7 Hz, 1H), 4.00 (dq, J = 8.3, 7.1 Hz, 1H), 3.75-3.60 (m, 3H), 3.45-3.35 (m, 3H), 2.05-1.80 (m, 4H), 1.24 (td, J = 7.0, 0.9 Hz, 1H). 19F NMR (377 MHz, DMSO-d 6) δ - 74.94 (9F), -127.34 (1F), -150.32 (1F), -157.02 (1F).
    • Example 42: N-(3-Chloro-4-fluorophenyl)-2-((2-(diethylamino)ethyl)amino)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0224
  • Methyl 2-((2-(diethylamino)ethyl)amino)-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-7-carboxylate was made analogously to Example 39 using N,N-diethylethane-1,2-diamine in place of N,N-dimethylpropane-1,3-diamine. The TFA salt of methyl 2-((2-(diethylamino)ethyl)amino)-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-7-carboxylate was isolated as a yellow oil. C21H34F2N4O3Si. 457.22 (M+1).
    Figure imgb0225
  • N-(3-chloro-4-fluorophenyl)-2-((2-(diethylamino)ethyl)amino)-4,5-difluoro-1H-benzo[d]imidazole-7-carboxamide was made analogously to Example 39 using methyl 2-((2-(diethylamino)ethyl)amino)-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-7-carboxylate in place of methyl 2-((3-(dimethylamino)propyl)amino)-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-7-carboxylate. The TFA salt of N-(3-chloro-4-fluorophenyl)-2-((2-(diethylamino)ethyl)amino)-4,5-difluoro-1H-benzo[d]imidazole-7-carboxamide was isolated as a white solid. C20H21ClF3N5O. 440.21/442/11 (M+1).
    Figure imgb0226
  • Example 42 was made analogously to Example 59 using N-(3-chloro-4-fluorophenyl)-2-((2-(diethylamino)ethyl)amino)-4,5-difluoro-1H-benzo[d]imidazole-7-carboxamide in place of N-(3-chloro-4-fluorophenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide . The TFA salt of N-(3-chloro-4-fluorophenyl)-2-((2-(diethylamino)ethyl)amino)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide was isolated as a white solid. C20H22ClF3N6O. 455.18/457.11 (M+1). 1H NMR (400 MHz, DMSO-d 6) δ 10.77 (s, 1H), 9.73 (s, 1H), 8.70 (s, 1H), 7.08 (t, J = 9.1 Hz, 1H), 6.97 (s, 1H), 6.92 (dd, J = 6.5, 2.7 Hz, 1H), 6.85 (dd, J = 12.2, 6.9 Hz, 1H), 6.53 (ddd, J = 9.0, 4.0, 2.7 Hz, 1H), 3.68 (m, 2H), 3.31 (m, 2H), 3.26 - 3.13 (m, 4H), 1.20 (t, J = 7.2 Hz, 6H). 19F NMR (376 MHz, DMSO-d 6) δ -74.9, -127.3, -150.3, -157.1.
    • Example 43: N-(3-Chloro-4-fluorophenyl)-2-((2-(dimethylamino)ethyl)amino)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0227
  • Methyl 2-((2-(dimethylamino)ethyl)amino)-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-7-carboxylate was made analogously to Example 39 using N,N-dimethylethane-1,2-diamine in place of N,N-dimethylpropane-1,3-diamine. The TFA salt of methyl 2-((2-(dimethylamino)ethyl)amino)-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-7-carboxylate was isolated as a yellow oil. C19H30F2N4O3Si. 429.17 (M+1).
    Figure imgb0228
  • N-(3-Chloro-4-fluorophenyl)-2-((2-(dimethylamino)ethyl)amino)-4,5-difluoro-1H-benzo[d]imidazole-7-carboxamide was made analogously to Example 39 using methyl 2-((2-(dimethylamino)ethyl)amino)-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-7-carboxylate in place of methyl 2-((3-(dimethylamino)propyl)amino)-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-7-carboxylate. The TFA salt of N-(3-chloro-4-fluorophenyl)-2-((2-(dimethylamino)ethyl)amino)-4,5-difluoro-1H-benzo[d]imidazole-7-carboxamide was isolated as a white solid. C18H17ClF3N5O. 412.19/414.09 (M+1).
    Figure imgb0229
  • Example 43 was made analogously to Example 59 using N-(3-chloro-4-fluorophenyl)-2-((2-(dimethylamino)ethyl)amino)-4,5-difluoro-1H-benzo[d]imidazole-7-carboxamide in place of N-(3-chloro-4-fluorophenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide . The TFA salt of N-(3-chloro-4-fluorophenyl)-2-((2-(dimethylamino)ethyl)amino)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide was isolated as a white solid. C18H18ClF3N6O. 427.14/429.09 (M+1). 1H NMR (400 MHz, DMSO-d 6) δ 10.78 (s, 1H), 9.74 (s, 1H), 8.71 (s, 1H), 7.09 (t, J = 10.7 Hz, 1H), 7.04 (br s, 1H), 6.93 (dd, J = 6.5, 2.7 Hz, 1H), 6.84 (dd, J = 12.2, 7.0 Hz, 1H), 6.53 (ddd, J = 9.0, 4.0, 2.7 Hz, 1H), 3.69 (q, J = 5.9 Hz, 2H), 3.31 (t, J = 5.8 Hz, 2H), 2.86 (s, 6H). 19F NMR (376 MHz, DMSO-d 6) δ -74.99 (9F), -127.32 (1F), -150.28 (1F), -156.83 (1F).
    • Example 44: N-(3-Chlorophenyl)-4,5-difluoro-N'-hydroxy-2-(1-methylpiperidin-3-yl)-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0230
  • Example 44 was made analogously to Example 53 using 1-methylpiperidine-3-carboxylic acid in place of 3-(dimethylamino)propanoic acid. The TFA salt of 4,5-difluoro-2-(1-methylpiperidin-3-yl)-1H-benzo[d]imidazole-7-carboxylic acid was isolated as a colorless oil. C14H15F2N3O2. 296.14/297.12 (M+1).
    Figure imgb0231
  • To a solution of 4,5-difluoro-2-(1-methylpiperidin-3-yl)-1H-benzo[d]imidazole-7-carboxylic acid (TFA salt, 63 mg, 0.19 mmol, 1 equiv), 3-chloroaniline (0.05 mL, 0.48 mmol, 2.5 equiv), and DIPEA (0.16 mL, 0.95 mmol, 5 equiv) in DMF (1 mL) was added HATU (87 mg, 0.23 mmol, 1.2 equiv) and the reaction was stirred overnight at room temperature. The crude product was purified by reverse phase HPLC (10-90% CH3CN/H2O) and the TFA salt of N-(3-chlorophenyl)-4,5-difluoro-2-(1-methylpiperidin-3-yl)-1H-benzo[d]imidazole-7-carboxamide was obtained as a white solid. C20H19ClF2N4O. 405.19/407.12 (M+1).
    Figure imgb0232
  • Example 44 was made analogously to Example 59 using N-(3-chloro-4-fluorophenyl)-4,5-difluoro-2-(1-methylpiperidin-3-yl)-1H-benzo[d]imidazole-7-carboxamide in place of N-(3-chloro-4-fluorophenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide . The TFA salt of N-(3-chlorophenyl)-4,5-difluoro-N'-hydroxy-2-(1-methylpiperidin-3-yl)-1H-benzo[d]imidazole-7-carboximidamide was isolated as a white solid. C20H20ClF2N5O. 420.22/422.17 (M+1).
    • Example 45: N-(3-Chloro-4-fluorophenyl)-6,7-difluoro-N'-hydroxy-2-(((3-methoxypropyl)amino)methyl)-1H-benzo[d]imidazole-4-carboximidamide
  • Figure imgb0233
  • Methyl 4,5-difluoro-2-(methoxymethyl)-1H-benzo[d]imidazole-7-carboxylate. A mixture of methyl 2,3-diamino-4,5-difluorobenzoate (2.0 g, 9.9 mmol) in methoxyacetic acid (23 mL) was stirred at 120 °C for 3 hr. To the mixture was added saturated sodium bicarbonate and the aqueous layer was washed three times with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, absorbed onto silica and purified by silica gel chromatography to give the desired product. C11H10F2N2O3. 257.3 (M+1).
    Figure imgb0234
  • N-(3-chloro-4-fluorophenyl)-4,5-difluoro-2-(methoxymethyl)-1H-benzo[d]imidazole-7-carboxamide. To a solution of the 3-chloro-4-fluoroaniline in (1.30 g, 8.90 mmol) in dichloroethane (60 mL) at 0 °C under nitrogen was added trimethylaluminum (2 M in heptane, 8.90 mL, 17.8 mmol) dropwise over 5 min. The solution was allowed to warm to room temperature and stirred for 30 min. The solution was cooled to 0 °C and to this solution was added methyl 4,5-difluoro-2-(methoxymethyl)-1H-benzo[d]imidazole-7-carboxylate (1.52 g, 5.93 mmol). The solution was stirred at 85 °C for 3 hr and, then, cooled to room temperature. Water and 10% citric acid were added and the resulting precipitate was filtered and dried on high vac to give the desired product. C16H11ClF3N3O2. 370.1 (M+1).
    Figure imgb0235
  • 4-(3-chloro-4-fluorophenyl)-3-(4,5-difluoro-2-(methoxymethyl)-1H-benzo[d]imidazol-7-yl)-1,2,4-oxadiazol-5(4H)-one. A mixture of N-(3-chloro-4-fluorophenyl)-4,5-difluoro-2-(methoxymethyl)-1H-benzo[d]imidazole-7-carboxamide (1.80 g, 4.86 mmol), phosphorous pentachloride (1.52 g, 7.29 mmol) in phosphoryl chloride (14 mL) and 1,2-dichloroethane (14 mL) was stirred at 80 °C for 2.5 hr. The reaction mixture was concentrated and suspended in ethanol (14 mL) and to this mixture was added 50% hydroxylamine in water (3.0 mL, 49 mmol). The reaction mixture stirred for 1.5 hr. Water was added to the reaction mixture and the resulting precipitate was collected by filtration and dried on high vac. The dried solid and carbonyl diimidazole (1.6 g, 9.7 mmol) was suspended in ethyl acetate (50 mL) and the reaction mixture stirred for 18 hr. The resulting solution was absorbed onto silica gel and purified by silica gel chromatography to give the desired product. C17H10ClF3N4O3. 411.0 (M+1).
    Figure imgb0236
  • 3-(2-(bromomethyl)-4,5-difluoro-1H-benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one and 4-(3-chloro-4-fluorophenyl)-3-(4,5-difluoro-2-(hydroxymethyl)-1H-benzo[d]imidazol-7-yl)-1,2,4-oxadiazol-5(4H)-one. To a mixture of 4-(3-chloro-4-fluorophenyl)-3-(4,5-difluoro-2-(methoxymethyl)-1H-benzo[d]imidazol-7-yl)-1,2,4-oxadiazol-5(4H)-one (937 mg, 2.28 mmol) in dichloromethane (16 mL) at 0 °C was added a solution of 1 M boron tribromide in dichloromethane (3.42 mL, 3.42 mmol). The reaction was allowed to warm to room temperature and stirred for 18 hr. The reaction mixture was diluted with dichloromethane and saturated sodium bicarbonate and the aqueous layer was washed three times with dichlromethane. The combined organic layers contained a precipitate that was filtered off to give 4-(3-chloro-4-fluorophenyl)-3-(4,5-difluoro-2-(hydroxymethyl)-1H-benzo[d]imidazol-7-yl)-1,2,4-oxadiazol-5(4H)-one (203 mg) as a white solid. The filtrate was dried over sodium sulfate, filtered, loaded onto silica gel column and purified by silica gel chromatography to give 3-(2-(bromomethyl)-4,5-difluoro-1H-benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one. C16H7BrClF3N4O2. 459.0 (M+1). C16H8ClF3N4O3. 397.1 (M+1).
    Figure imgb0237
  • N-(3-chloro-4-fluorophenyl)-6,7-difluoro-N'-hydroxy-2-(((3-methoxypropyl)amino)methyl)-1H-benzo[d]imidazole-4-carboximidamide. A solution of 3-(2-(bromomethyl)-4,5-difluoro-1H-benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one (12 mg, 0.026 mmol) and 3-methoxypropylamine (0.027 mL, 0.26 mmol) in acetonitrile (1 mL) was stirred at 65 °C for 10 min. The reaction was concentrated. The residue was brought up in tetrahydrofuran (0.3 mL) and water (0.3 mL). To this solution was added 2 N sodium hydroxide (0.19 mL, 0.34 mmol) and the reaction mixture stirred for 10 min. To the mixture was added acetic acid (0.05 mL) and the solution was loaded directly onto a prep HPLC for purification to give the desired product. C19H19ClF3N5O2. 442.1 (M+1).
    • Example 46: N-(3-Chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-(hydroxymethyl)-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0238
  • To a solution of 4-(3-chloro-4-fluorophenyl)-3-(4,5-difluoro-2-(hydroxymethyl)-1H-benzo[d]imidazol-7-yl)-1,2,4-oxadiazol-5(4H)-one (20 mg, 0.050 mmol) in tetrahydrofuran (0.4 mL) and water (0.4 mL) was added 2 N sodium hydroxide (0.38 mL, 0.76 mmol) and the reaction mixture stirred for 10 min. To the mixture was added acetic acid (0.06 mL) and the solution was loaded directly onto a prep HPLC for purification to give the desired product. C15H10ClF3N4O2. 371.0 (M+1). 1H NMR (400 MHz, DMSO-d 6) δ 10.93 (s, 1H), 8.80 (s, 1H), 7.16 (dd, J = 12.0, 7.0 Hz, 1H), 7.04 (t, J = 9.1 Hz, 1H), 6.93 (dd, J = 6.5, 2.7 Hz, 1H), 6.49 (ddd, J = 9.0, 4.1, 2.7 Hz, 1H), 4.63 (s, 2H).
    • Example 47: 2-(Aminomethyl)-N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0239
  • Example 47 was made analogously to Example 45 using 0.5 M ammonia in dioxane in place of 3-methoxypropylamine. C15H11ClF3N5O. 370.1 (M+1).
    • Example 48: N-(3-Chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((methylamino)methyl)-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0240
  • Example 48 was made analogously to Example 45 using 2 M methylamine in tetrahydrofuran in place of 3-methoxypropylamine. C16H13ClF3N5O. 384.0 (M+1). 1H NMR (400 MHz, DMSO-d 6) δ 12.84 (s, 1H), 10.92 (s, 1H), 9.21 (s, 2H), 8.82 (s, 1H), 7.34 - 7.17 (m, 1H), 7.04 (t, J = 9.1 Hz, 1H), 6.90 (dd, J= 6.6, 2.7 Hz, 1H), 6.48 (dt, J = 9.0, 3.5 Hz, 1H), 4.40 (t, J = 5.8 Hz, 2H), 2.65 (s, 3H).
    • Example 49: N-(3-Chloro-4-fluorophenyl)-2-(((cyclopropylmethyl)amino)methyl)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0241
  • Example 49 was made analogously to Example 45 using cyclopropylmethylamine in place of 3-methoxypropylamine. C19H17ClF3N5O.424.0 (M+1).
    • Example 50: N-(3-Chloro-4-fluorophenyl)-2-((ethylamino)methyl)-6,7-difluoro-N'-hydroxy-1H-benzo[d]imidazole-4-carboximidamide
  • Figure imgb0242
  • Example 50 was made analogously to Example 45 using 2 M ethylamine in tetrahydrofuran in place of 3-methoxypropylamine. C17H15ClF3N5O. 398.0 (M+1). 1H NMR (400 MHz, DMSO-d 6) δ 12.85 (s, 1H), 10.92 (s, 1H), 9.25 (s, 2H), 8.82 (s, 1H), 7.33 - 7.20 (m, 1H), 7.05 (t, J = 9.0 Hz, 1H), 6.91 (dd, J = 6.5, 2.7 Hz, 1H), 6.50 (dt, J = 9.0, 3.6 Hz, 1H), 4.43 (t, J = 5.9 Hz, 2H), 3.11 - 2.95 (m, 2H), 1.21 (t, J = 7.2 Hz, 3H).
    • Example 51: N-(3-Chloro-4-fluorophenyl)-6,7-difluoro-N-hydroxy-2-((isopropylamino)methyl)-1H-benzo[d]imidazole-4-carboximidamide
  • Figure imgb0243
  • Example 51 was made analogously to Example using isopropylamine in place of 3-methoxypropylamine. C18H17ClF3N5O. 412.1 (M+1). 1H NMR (400 MHz, DMSO-d 6) δ 12.85 (s, 1H), 10.94 (s, 1H), 9.25 (s, 2H), 8.82 (s, 1H), 7.33 - 7.20 (m, 1H), 7.06 (t, J = 9.0 Hz, 1H), 6.90 (dd, J = 6.5, 2.7 Hz, 1H), 6.50 (dt, J = 9.1, 3.5 Hz, 1H), 4.49 - 4.37 (m, 2H), 3.48 - 3.33 (m, 1H), 1.26 (d, J = 6.5 Hz, 6H).
    • Example 52: N-(3-Chloro-4-fluorophenyl)-2-((dimethylamino)methyl)-6,7-difluoro-N'-hydroxy-1H-benzo[d]imidazole-4-carboximidamide
  • Figure imgb0244
  • Example 52 was made analogously to Example 45 using dimethylamine in place of 3-methoxypropylamine. C17H15ClF3N5O. 398.1 (M+1). 1H NMR (400 MHz, DMSO-d 6) δ12.93 (s, 1H), 10.93 (s, 1H), 10.28 (s, 1H), 8.83 (s, 1H), 7.40 - 7.23 (m, 1H), 7.03 (t, J = 9.1 Hz, 1H), 6.95 (dd, J = 6.6, 2.7 Hz, 1H), 6.49 (dt, J = 9.0, 3.5 Hz, 1H), 4.56 (s, 2H), 2.83 (s, 6H).
    • Example 53: N-(3-Chloro-4-fluorophenyl)-2-(2-(dimethylamino)ethyl)-6,7-difluoro-N'-hydroxy-1H-benzo[d]imidazole-4-carboximidamide
  • Figure imgb0245
  • 2-(2-(dimethylamino)ethyl)-6,7-difluoro-1H-benzo[d]imidazole-4-carboxylic acid. A mixture of methyl 2,3-diamino-4,5-difluorobenzoate (2.0g, 9.89mmol) and 3-(dimethylamino)propanoic acid (6.08g, 39.6mmol) in concentrated hydrochloric acid was stirred at 120°C overnight in a sealed screw-top flask. The reaction was concentrated under reduced pressure. Cured product was used as is in next step without purification. C12H13F2N3O2. 270.10 (M+1).
    Figure imgb0246
  • N-(3-chloro-4-fluorophenyl)-2-(2-(dimethylamino)ethyl)-6,7-difluoro-1H-benzo[d]imidazole-4-carboxamide. A mixture of 2-(2-(dimethylamino)ethyl)-6,7-difluoro-1H-benzo[d]imidazole-4-carboxylic acid (300 mg, 1.114mmol), 3-chloro-4-fluoroaniline (300 mg, 1.114mmol), bis(2-oxo-3-oxazolidinyl)phosphinic chloride (567mg, 2.23mmol) and diisopropylethylamine (1.94mL, 11.1 mmol) in dichloromethane (8 mL) was stirred for 2hr. The reaction mixture was filtered and absorbed onto silica gel and purified by silica gel chromatography to give the desired product. C18H16ClF3N4O.
    Figure imgb0247
  • N-(3-chloro-4-fluorophenyl)-2-(2-(dimethylamino)ethyl)-6,7-difluoro-N'-hydroxy-1H-benzo[d]imidazole-4-carboximidamide. Example 53 was made analogously to Example 95 C18H17ClF3N5O. 411.11 (M+1). 1H NMR (400 MHz, DMSO-d 6) δ 10.92 (s, 1H), 8.78 (s, 1H), 7.17 (dd, J = 12.0, 7.0 Hz, 1H), 7.04 (t, J = 9.1 Hz, 1H), 6.93 (dd, J = 6.6, 2.7 Hz, 1H), 6.50 (ddd, J = 9.0, 4.1, 2.7 Hz, 1H), 3.53 (t, J = 7.5 Hz, 2H), 3.26 (t, J = 7.6 Hz, 2H), 2.83 (s, 6H)
    • Example 54: N-(3-Bromo-4-fluorophenyl)-2-(2-(dimethylamino)ethyl)-6,7-difluoro-N'-hydroxy-1H-benzo[d]imidazole-4-carboximidamide
  • Figure imgb0248
  • N-(3-bromo-4-fluorophenyl)-2-(2-(dimethylamino)ethyl)-6,7-difluoro-1H-benzo[d]imidazole-4-carboxamide was made analogously to Example 53 using 3-bromo-4-fluoroaniline in place of 3-chloro-4-fluoroaniline. C18H16BrF3N4O. 441.1 (M+1).
    Figure imgb0249
  • N-(3-bromo-4-fluorophenyl)-2-(2-(dimethylamino)ethyl)-6,7-difluoro-N'-hydroxy-1H-benzo[d]imidazole-4-carboximidamide. Example 54 was made analogously to Example 95. C18H17BrF3N5O. 456.1 (M+1). 1H NMR (400 MHz, DMSO-d 6) δ 10.89 (s, 1H), 8.76 (s, 1H), 7.17 (dd, J = 11.9, 7.0 Hz, 1H), 7.07 (dd, J = 6.1, 2.7 Hz, 1H), 7.00 (t, J= 8.8 Hz, 1H), 6.53 (ddd, J = 8.9, 4.1, 2.7 Hz, 1H), 3.53 (t, J = 7.5 Hz, 2H), 3.26 (t, J = 7.5 Hz, 2H), 2.83 (s, 6H).
    • Example 55: N-(3-Bromophenyl)-2-(2-(dimethylamino)ethyl)-6,7-difluoro-N'-hydroxy-1H-benzo[d]imidazole-4-carboximidamide
  • Figure imgb0250
  • N-(3-bromophenyl)-2-(2-(dimethylamino)ethyl)-6,7-difluoro-1H-benzo[d]imidazole-4-carboxamide was made analogously to Example 53 using 3-bromoaniline in place of 3-chloro-4-fluoroaniline. C18H16BrF3N4O. 423.1 (M+1).
    Figure imgb0251
  • N-(3-bromophenyl)-2-(2-(dimethylamino)ethyl)-6,7-difluoro-N'-hydroxy-1H-benzo[d]imidazole-4-carboximidamide. Example 55 was made analogously to Example 95. C18H18BrF2N5O. 438.10. 1H NMR (400 MHz, DMSO-d 6) δ 10.98 (s, 1H), 8.78 (s, 1H), 7.22 - 7.07 (m, 1H), 7.00 - 6.85 (m, 3H), 6.55 - 6.40 (m, 1H), 3.54 (t, J = 7.5 Hz, 2H), 3.35 - 3.20 (m, 2H), 2.84 (s, 6H).
    • Example 56: N-(3-Chlorophenyl)-2-(2-(dimethylamino)ethyl)-6,7-difluoro-N'-hydroxy-1H-benzo[d]imidazole-4-carboximidamide
  • Figure imgb0252
  • N-(3-chlorophenyl)-2-(2-(dimethylamino)ethyl)-6,7-difluoro-1H-benzo[d]imidazole-4-carboxamide was made analogously to Example 53 using 3-chloroaniline in place of 3-chloro-4-fluoroaniline. C18H17ClF2N4O. 379.11(M+1).
    Figure imgb0253
  • N-(3-chlorophenyl)-2-(2-(dimethylamino)ethyl)-6,7-difluoro-N'-hydroxy-1H-benzo[d]imidazole-4-carboximidamide. Example 56 was made analogously to Example 95 C18H18ClF2N5O. 394.12 (M+1). 1H NMR (400 MHz, DMSO-d 6) δ 10.94 (s, 1H), 8.78 (s, 1H), 7.14 (dd, J = 12.0, 7.0 Hz, 1H), 7.00 (t, J = 8.0 Hz, 1H), 6.86 - 6.74 (m, 2H), 6.51 - 6.38 (m, 1H), 3.54 (t, J = 7.5 Hz, 2H), 3.27 (t, J = 7.5 Hz, 2H), 2.83 (s, 6H).
    • Example 57: N-(3-Chloro-4-fluorophenyl)-6,7-difluoro-N'-hydroxy-2-(2-(methylamino)ethyl)-1H-benzo[d]imidazole-4-carboximidamide
  • Figure imgb0254
  • Ethyl 2-(7-((3-chloro-4-fluorophenyl)carbamoyl)-4,5-difluoro-1H-benzo[d]imidazol-2-yl)acetate was made analogously to Example 53 using 2,3-diamino-N-(3-chloro-4-fluorophenyl)-4,5-difluorobenzamide. C18H13ClF3N3O3. 412.10 (M+1).
    Figure imgb0255
  • N-(3-chloro-4-fluorophenyl)-4,5-difluoro-2-(2-hydroxyethyl)-1H-benzo[d]imidazole-7-carboxamide was made analogously to Example 183 using Ethyl 2-(7-((3-chloro-4-fluorophenyl)carbamoyl)-4,5-difluoro-1H-benzo[d]imidazol-2-yl)acetate. C16H11ClF3N3O2. 370.10 (M+1).
    Figure imgb0256
  • N-(3-chloro-4-fluorophenyl)-4,5-difluoro-2-(2-((triisopropylsilyl)oxy)ethyl)-1H-benzo[d]imidazole-7-carboxamide was made analogously to Example 183 using N-(3-chloro-4-fluorophenyl)-4,5-difluoro-2-(2-hydroxyethyl)-1H-benzo[d]imidazole-7-carboxamide. C25H31ClF3N3O2Si. 526.18 (M+1).
    Figure imgb0257
  • N-(3-chloro-4-fluorophenyl)-4,5-difluoro-2-(2-((triisopropylsilyl)oxy)ethyl)-1H-benzo[d]imidazole-7-carbothioamide was made analogously to Example 183 using N-(3-chloro-4-fluorophenyl)-4,5-difluoro-2-(2-((triisopropylsilyl)oxy)ethyl)-1H-benzo[d]imidazole-7-carboxamide. C25H31ClF3N3OSSi. 542.16 (M+1).
    Figure imgb0258
  • 4-(3-chloro-4-fluorophenyl)-3-(4,5-difluoro-2-(2-((triisopropylsilyl)oxy)ethyl)-1H-benzo[d]imidazol-7-yl)-1,2,4-oxadiazol-5(4H)-one was made analogously to Example 183 using N-(3-chloro-4-fluorophenyl)-4,5-difluoro-2-(2-((triisopropylsilyl)oxy)ethyl)-1H-benzo[d]imidazole-7-carbothioamide. C26H30ClF3N4O3Si. 567.17 (M+1).
    Figure imgb0259
  • 2-(7-(4-(3-chloro-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-4,5-difluoro-1-(methylsulfonyl)-1H-benzo[d]imidazol-2-yl)ethyl methanesulfonate was made analogously to Example 112 using 4-(3-chloro-4-fluorophenyl)-3-(4,5-difluoro-2-(2-((triisopropylsilyl)oxy)ethyl)-1H-benzo[d]imidazol-7-yl)-1,2,4-oxadiazol-5(4H)-one. C19H14ClF3N4O7S2. 567.00 (M+1).
    Figure imgb0260
  • N-(3-chloro-4-fluorophenyl)-6,7-difluoro-N'-hydroxy-2-(2-(methylamino)ethyl)-1H-benzo[d]imidazole-4-carboximidamide. Example 57 was made analogously to Example 112 using 2-(7-(4-(3-chloro-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-4,5-difluoro-1-(methylsulfonyl)-1H-benzo[d]imidazol-2-yl)ethyl methanesulfonate in place of 2-(7-(4-(3-chloro-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-3-(methylsulfonyl)-3H-imidazo[4,5-b]pyridin-2-yl)ethyl methanesulfonate. C16H16ClFN6O. 363.11 (M+1).
    • Example 58: N-(3-Chloro-4-fluorophenyl)-2-(2-(diethylamino)ethyl)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0261
  • Example 58 was made analogously to Example 57 using 2-(7-(4-(3-chloro-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-4,5-difluoro-1-(methylsulfonyl)-1H-benzo[d]imidazol-2-yl)ethyl methanesulfonate and diethylamine in place of 2-(7-(4-(3-chloro-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-3-(methylsulfonyl)-3H-imidazo[4,5-b]pyridin-2-yl)ethyl methanesulfonate and methylamine. C20H21ClF3N5O. 440.14 1H NMR (400 MHz, DMSO-d 6) δ 10.85 (s, 1H), 8.78 (s, 1H), 7.18 (dd, J = 11.9, 6.9 Hz, 1H), 7.03 (t, J = 9.0 Hz, 1H), 6.94 (dd, J = 6.6, 2.7 Hz, 1H), 6.48 (ddd, J = 9.0, 4.0, 2.7 Hz, 1H), 3.50 (t, J = 7.6 Hz, 2H), 3.24 (t, J = 7.7 Hz, 2H), 3.19 (q, J = 8.3, 7.3 Hz, 4H), 1.20 (t, J = 7.3 Hz, 6H).
    • Example 59: N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0262
  • 1H-imidazo[4,5-b]pyridine-7-carboxylic acid (300 mg, 2.0 mmol), 3-chloro-4-fluoroaniline (2.0 mmol), and HATU (2.4 mmol) were dissolved in DMF (5 mL) and DIPEA (6 mmol) was added. The reaction was allowed to stir at rt overnight. The reaction was quenched with saturated sodium bicarbonate solution (5 mL) and the reaction was extracted with EtOAc (3x5 mL). Combined organic layers were washed with brine (1x8 mL) and concentrated in vacuo. The crude material was purified by column chromatography (EtOAc/hex) to give N-(3-chloro-4-fluorophenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide.
  • N-(3-chloro-4-fluorophenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide (122 mg, 0.42 mmol) and PCl5 (0.63 mmol) was dissolved in POCl3 (2 mL) and heated to 85 °C for 12 hours. The reaction was cooled to rt and concentrated in vacuo. The residue was dissolved in a pre-mixed solution of hydroxylamine (50% aqueous solution, 4.0 mmol) and ethanol (2 mL) and the reaction was allowed to stir at rt for 10 minutes. The reaction was concentrated in vacuo and purified by reverse-phase HPLC to give N-(3-chloro-4-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide as a white solid. C13H9ClFN5O. 306.0/308.0 (M+1). 1H NMR (400 MHz, DMSO-d 6) δ 11.14 (s, 1H), 8.92 (d, J = 1.9 Hz, 1H), 8.64 (s, 1H), 8.43 - 8.39 (m, 1H), 7.28 - 7.23 (m, 1H), 7.03 (t, J = 9.1 Hz, 1H), 6.98 - 6.92 (m, 1H), 6.51 (dt, J = 8.9, 3.4 Hz, 1H).
    • Example 60: N-(5-Chloro-2-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0263
  • Example 60 was made analogously to Example 59 using 5-chloro-2-fluoroaniline in place of 3-chloro-4-fluoroaniline. C13H9ClFN5O. 306.1/308.2 (M+1). 1H NMR (400 MHz, Methanol-d 4) δ 8.88 (s, 1H), 8.46 (d, J = 5.3 Hz, 1H), 7.35 (d, J = 5.3 Hz, 1H), 7.01 - 6.95 (m, 2H), 6.92 - 6.85 (m, 1H).
    • Example 61: N-(5-Bromo-2,4-difluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0264
  • Example 61 was made analogously to Example 59 using 5-bromo-2,4-difluoroaniline in place of 3-chloro-4-fluoroaniline. C13H8BrF2N5O. 368.0/370.0 (M+1). 1H NMR (400 MHz, DMSO-d 6) δ 11.03 (s, 1H), 8.71 (s, 1H), 8.59 (s, 1H), 8.36 (d, J = 4.8 Hz, 1H), 7.34 - 7.21 (m, 3H).
    • Example 62: N-(5-Chloro-2,4-difluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0265
  • Example 62 was made analogously to Example 59 using 5-chloro-2,4-difluoroaniline in place of 3-chloro-4-fluoroaniline. C13H8ClF2N5O. 324.0/326.1 (M+1). 1H NMR (400 MHz, DMSO-d 6) δ 11.08 (s, 1H), 8.71 (d, J = 17.2 Hz, 2H), 8.42 - 8.34 (m, 1H), 7.34 (dd, J = 10.7, 9.3 Hz, 1H), 7.28 (d, J = 5.0 Hz, 1H), 7.15 (t, J = 8.2 Hz, 1H).
    • Example 63: N-(3,5-Dichloro-4-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0266
  • Example 63 was made analogously to Example 59 using 3,5-dichloro-4-fluoroaniline in place of 3-chloro-4-fluoroaniline. C13H8Cl2FN5O. 340.1/342.1 (M+1). 1H NMR (400 MHz, DMSO-d 6) δ 11.26 (s, 1H), 10.10 (s, 1H), 9.07 (d, J = 1.1 Hz, 1H), 8.53 (s, 1H), 8.45 - 8.37 (m, 1H), 7.31 (d, J = 5.2 Hz, 1H), 6.81 - 6.73 (m, 2H).
    • Example 64: N-(3-Chloro-2,4-difluorophenyl)-N'-hydroay-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0267
  • Example 64 was made analogously to Example 59 using 3-chloro-2,4-difluoroaniline in place of 3-chloro-4-fluoroaniline. C13H8ClF2N5O. 324.1/326.1 (M+1). 1H NMR (400 MHz, DMSO-d 6) δ 10.99 (s, 0H), 8.67 (s, 1H), 8.51 (s, 1H), 8.34 (dd, J = 5.0, 2.3 Hz, 1H), 7.22 (s, 1H), 7.04 (t, J = 9.0 Hz, 1H), 6.84 (s, 1H).
    • Example 65: N-(3-Cyclopropyl-4-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0268
  • Example 65 was made analogously to Example 59 using 3-cyclopropyl-4-fluoroaniline in place of 3-chloro-4-fluoroaniline. C16H14FN5O. 312.1 (M+1).
    • Example 66: N'-Hydroxy-N-(4-(trifluoromethoxy)phenyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0269
  • Example 66 was made analogously to Example 59 using 4-(trifluoromethoxy)aniline in place of 3-chloro-4-fluoroaniline. C14H10F3N5O2. 338.1 (M+1).
    • Example 67: N-(Benzofuran-4-yl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0270
  • Example 67 was made analogously to Example 59 using benzofuran-4-amine in place of 3-chloro-4-fluoroaniline. C15H11N5O2. 294.1 (M+1). 1H NMR (400 MHz, DMSO-d 6) δ 11.32 (s, 1H), 8.92 (s, 1H), 8.86 (s, 1H), 8.34 (dd, J = 5.2, 2.7 Hz, 1H), 7.83 (d, J = 2.2 Hz, 1H), 7.16 - 7.09 (m, 2H), 7.06 (dd, J = 2.3, 1.0 Hz, 1H), 6.95 (t, J = 8.0 Hz, 1H), 6.36 (d, J = 7.8 Hz, 1H).
    • Example 68: N-(Benzofuran-6-yl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0271
  • Example 68 was made analogously to Example 59 using benzofuran-6-amine in place of 3-chloro-4-fluoroaniline. C15H11N5O2. 294.1 (M+1). 1H NMR (400 MHz, DMSO-d 6) δ 11.17 (s, 1H), 8.89 (d, J = 33.4 Hz, 2H), 8.40 (d, J = 6.1 Hz, 1H), 7.79 - 7.74 (m, 1H), 7.30 (dd, J = 8.6, 2.0 Hz, 1H), 7.24 (t, J = 5.9 Hz, 1H), 6.90 (t, J = 2.5 Hz, 1H), 6.76 (dd, J = 2.2, 1.1 Hz, 1H), 6.69 (dt, J = 8.4, 1.9 Hz, 1H).
    • Example 69: N-(Benzofuran-7-yl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0272
  • Example 69 was made analogously to Example 59 using benzofuran-7-amine in place of 3-chloro-4-fluoroaniline. C15H11N5O2. 294.1 (M+1).
    • Example 70: N-(benzofuran-5-yl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0273
  • Example 70 was made analogously to Example 59 using benzofuran-5-amine in place of 3-chloro-4-fluoroaniline. C15H11N5O2. 294.1 (M+1).
    • Example 71: N-(5-Bromo-2-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0274
  • Example 71 was made analogously to Example 59 using acid and 5-bromo-2-fluoroaniline in place of 3-chloro-4-fluoroaniline. C13H9BrFN5O. 350.1/352.1 (M+1). 1H NMR (400 MHz, DMSO-d 6) δ 11.16 (s, 1H), 10.06 (s, 1H), 8.74 (s, 1H), 8.57 (s, 1H), 8.35 (d, J = 5.1 H, 1H), 7.25 (s, 1H), 7.14 - 6.92 (m, 3H).
    • Example 72: N-(3-Bromo-5-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0275
  • Example 72 was made analogously to Example 59 using 5-bromo-3-fluoroaniline in place of 3-chloro-4-fluoroaniline. C13H9BrFN5O. 350.1/352.1 (M+1). 1H NMR (400 MHz, DMSO-d 6) δ 11.32 (s, 1H), 9.08 (s, 1H), 8.55 (s, 1H), 8.37 (d, J = 5.1 Hz, 1H), 7.23 (d, J = 5.1 Hz, 1H), 6.84 - 6.75 (m, 1H), 6.66 (t, J = 1.9 Hz, 1H), 6.30 (dt, J = 11.3, 2.1 Hz, 1H).
    • Example 73: N'-Hydroxy-N-(3-(trifluoromethyl)phenyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0276
  • Example 73 was made analogously to Example 59 using 3-(trifluoromethyl)aniline in place of 3-chloro-4-fluoroaniline. C14H10F3N5O. 322.1 (M+1). 1H NMR (400 MHz, DMSO-d 6) δ 11.34 (s, 1H), 9.13 (s, 1H), 8.77 (s, 1H), 8.43 (d, J = 5.1 Hz, 1H), 7.29 (d, J = 5.1 Hz, 1H), 7.27 - 7.13 (m, 1H), 7.13 - 7.02 (m, 2H), 6.90 - 6.71 (m, 1H).
    • Example 74: N-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0277
  • Example 74 was made analogously to Example 59 using 2,2-difluorobenzo[d][1,3]dioxol-5-amine in place of 3-chloro-4-fluoroaniline.
  • N-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide. C14H9F2N5O3. 334.1 (M+1). 1H NMR (400 MHz, DMSO-d 6) δ 11.00 (d, J = 13.0 Hz, 1H), 8.86 (s, 1H), 8.46 (s, 1H), 8.34 (d, J = 5.0 Hz, 1H), 7.22 (d, J = 31.8 Hz, 1H), 7.00 (d, J = 8.7 Hz, 1H), 6.78 (d, J = 2.2 Hz, 1H), 6.34 (dd, J = 8.7, 2.3 Hz, 1H).
    • Example 75: N-(3-Fluoro-5-(trifluoromethyl)phenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0278
  • Example 75 was made analogously to Example 59 using 3-fluoro-5-(trifluoromethyl)aniline in place of 3-chloro-4-fluoroaniline. C14H9F4N5O. 340.1 (M+1).
    • Example 76: N-(2,5-Dichlorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0279
  • 1H-imidazo[4,5-b]pyridine-7-carboxylic acid (200 mg, 1.0 mmol) and 2,5-dichloroaniline (2.0 mmol) were dissolved in DCM (3 mL) and cooled to 0 °C. Triethylamine (4.0 mmol) was added dropwise followed by POCl3 (2.0 mmol) and the reaction was allowed to slowly come to rt and stir for 15 mins. The reaction was quenched with saturated sodium bicarbonate solution and extracted with EtOAc (3x5 mL). Combined organic layers were washed with brine (1x7 mL) and concentrated in vacuo. The crude material was purified by column chromatography (EtOAc/hex) to give N-(2,5-dichlorophenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide.
  • N-(2,5-dichlorophenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide (40 mg, 0.13 mmol) was dissolved in POCl3 (2 mL) and PCl5 (0.195 mmol) was added. The reaction was heated to 80 °C overnight, allowed to cool to rt, and concentrated in vacuo. The crude was dissolved in a pre-mixed solution of hydroxylamine (50% in water, 1.0 mmol) and ethanol (2 mL) and allowed to stir at rt for 10 mins then concentrated in vacuo. The crude was purified by reverse-phase HPLC to give N-(2,5-dichlorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide. C13H9Cl2N5O. 322.0/324.0 (M+1). 1H NMR (400 MHz, DMSO-d 6) δ 11.50 (s, 1H), 8.80 (s, 1H), 8.71 (s, 1H), 8.48 - 8.39 (m, 1H), 7.43 - 7.34 (m, 2H), 6.98 (dd, J = 8.6, 2.4 Hz, 1H), 6.69 (d, J = 3.2 Hz, 1H).
    • Example 77: N-(6-Fluoro-[1,1'-biphenyl]-3-yl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0280
  • 1H-imidazo[4,5-b]pyridine-7-carboxylic acid (1.5g, 9.0 mmol), 3-bromo-4-fluoroaniline (11.0 mmol), and HATU (12.0 mmol) were dissolved in DMF (15.0 mL) and DIPEA (28.0 mmol) was added and the reaction was allowed to stir overnight at rt. The reaction was quenched with saturated sodium bicarb solution and the precipitate was isolated by vacuum filtration. The precipitate was washed with water followed by diethyl ether to give N-(3-bromo-4-fluorophenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide as a yellow powder.
  • N-(3-bromo-4-fluorophenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide (150 mg, 0.448 mmol) and phenyl boronic acid (2.0 mmol) was dissolved in degassed THF (2.0 mL) and water (0.50 mL). PdCl2(dppf) (0.090 mmol) and K2CO3 (2.0 mmol) were added and the reaction was heated to 65 °C overnight. The reaction was allowed to cool to rt and quenched with saturated bicarb solution. The solution was extracted with EtOAc (3 x 4 mL) and combined organic layers were washed with brine (1x 5 ((EtOAc/hex) to give N-(6-fluoro-[1,1'-biphenyl]-3-yl)-1H-imidazo[4,5-b]pyridine-7-carboxamide.
  • N-(6-fluoro-[1,1'-biphenyl]-3-yl)-1H-imidazo[4,5-b]pyridine-7-carboxamide (100 mg, 0.301 mmol) was dissolved in POCl3, PCl5 (2.0 mmol) was added, and the reaction was heated to 80 °C overnight. The reaction was allowed to cool to rt and concentrated in vacuo. The crude was dissolved in a pre-mixed solution of hydroxylamine (50% in water, 3.0 mmol) and ethanol (2 mL) and allowed to stir at rt for 10 mins. The reaction was purified by reverse-phase HPLC to give N-(6-fluoro-[1,1'-biphenyl]-3-yl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide. C19H14FN5O. 348.2 (M+1).
    • Example 78: N-(3-(But-1-yn-1-yl)-4-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0281
  • N-(3-bromo-4-fluorophenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide (100 mg, 0.298 mmol), PdCl2(PPh3)2 (0.015 mmol), and CuI (0.0298 mmol) were dissolved in degassed DMF (0.75 mL) and DIPEA (3.0 mmol) was added. But-1-yne was bubbled through the reaction for 5 mins and then removed. The reaction was allowed to stir overnight under an atmosphere of but-1-yne. The reaction was quenched with water and extracted with EtOAc (3x 3 mL). The combined organic layers were washed with brine (1x5 mL) and concentrated in vacuo. The crude was purified by column chromatography (EtOAc/hex) to give N-(3-(but-1-yn-1-yl)-4-fluorophenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide (57 mg, 62%).
  • N-(3-(but-1-yn-1-yl)-4-fluorophenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide (56 mg, 0.182 mmol) was dissolved in POCl3 (2 mL) and PCl5 (0.272 mmol) was added and the reaction was heated to 80 °C for 45 mins. The reaction was allowed to cool to rt and concentrated in vacuo. The material was dissolved in a pre-mixed solution of hydroxylamine (50% in water, 2.0 mmol) and ethanol (2 mL) and allowed to stir at rt for 10 mins. The reaction was purified by reverse-phase HPLC to giveN-(3-(but-1-yn-1-yl)-4-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide. C17H14FN5O. 324.2 (M+1).
    • Example 79: N-(3-(Cyclopropylethynyl)-4-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0282
  • Example 79 was made analogously to Example 78 using ethynylcyclopropane (5 eq) in place of but-1-yne. C18H14FN5O. 336.1 (M+1).
    • Example 80: N-(3-Bromophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0283
  • N-(3-bromophenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide. To a solution of 1H-imidazo[4,5-b]pyridine-7-carboxylic acid (0.102 g, 0.625 mmol), 3-bromoaniline (0.07 mL, 0.625 mmol), HOBt (0.101 g, 0.750 mmol) and DIEA (0.27 mL, 1.56 mmol) in DMF (3 mL) was added EDC (0.16 mL, 0.75 mmol). The mixture stirred at room temperature for 16 h. The mixture was diluted with sat. bicarb solution and the solid was isolated via filtration. The solid was suspended in 10% citric acid solution and then isolated via filtration. The filter cake was rinsed with water and dried under vacuum to yield the desired product. C13H9BrN4O. 317.0/319.0 [M+1]+.
    Figure imgb0284
  • N-(3-bromophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide. To a mixture of N-(3-bromophenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide (0.062 g, 0.195 mmol) and phosphoryl chloride (0.18 mL, 1.95 mmol) in DCE (2 mL) was added phosphorus pentachloride (0.061 g, 0.293 mmol). The mixture was stirred at 80 °C for 2 h. The mixture was cooled to rt and concentrated under reduced pressure. The residue was taken up in EtOH (3 mL) and hydroxylamine (0.12 mL of a 50 w/w% solution in water, 1.96 mmol) was added. The mixture stirred 2 h at rt. The mixture was concentrated and the residue was dissolved in DMSO/water and purified via preparative HPLC to yield the desired product. C13H10BrN5O. 332.0/334.0 [M+1]+. 1H NMR (400 MHz, DMSO-d 6) δ 11.25 (br s, 1H), 8.94 (br s, 1H), 8.71 (br s, 1H), 8.42 (dd, J = 5.0, 2.5 Hz, 1H), 7.26 (dd, J = 5.2, 2.2 Hz, 1H), 7.01 - 6.98 (m, 1H), 6.96 - 6.91 (m, 2H), 6.51 (ddd, J = 4.9, 3.8, 2.2 Hz, 1H).
    • Example 81: N-(3-Bromo-4-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0285
  • N-(3-bromo-4-fluorophenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide. To a solution of 1H-imidazo[4,5-b]pyridine-7-carboxylic acid (0.097 g, 0.595 mmol), 3-bromo-4-fluoroaniline (0.114 g, 0.597 mmol), HOBt (0.099 g, 0.729 mmol) and DIEA (0.26 mL, 1.49 mmol) in DMF (3 mL) was added EDC (0.15 mL, 0.71 mmol). The mixture stirred at room temperature for 16 h. The mixture was diluted with sat. bicarb solution and the solid was isolated via filtration. The solid was taken up in DCM/MeCN, concentrated onto silica gel, and purified via flash chromatography on silica gel to give the desired product. C13H8BrFN4O. 335.0/337.0 [M+1]+.
    Figure imgb0286
  • N-(3-bromo-4-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide. Example 81 was synthesized analogously to Example 80, using N-(3-bromo-4-fluorophenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide in place of N-(3-bromophenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide. (C13H9BrFN5O. 350.0/352.0 [M+1]+. 1H NMR (400 MHz, DMSO-d 6) δ 11.18 (br s, 1H), 8.94 (br s, 1H), 8.69 (br s, 1H), 8.42 (d, J = 5.1 Hz, 1H), 7.26 (d, J = 5.1 Hz, 1H), 7.09 (dd, J = 6.1, 2.7 Hz, 1H), 7.00 (t, J = 8.8 Hz, 1H), 6.54 (ddd, J = 8.9, 4.1, 2.7 Hz, 1H).
    • Example 82: N-(3-Chlorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0287
  • N-(3-chlorophenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide was synthesized analogously to Example 80 using 3-chloroaniline in place of 3-bromoaniline. C13H9ClN4O. 273.0 [M+1]+.
    Figure imgb0288
  • N-(3-chlorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide. Example 82 was synthesized analogously to Example 80, using N-(3-chlorophenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide in place of N-(3-bromophenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide. C13H10ClN5O. 288.0 [M+1]+. 1H NMR (400 MHz, DMSO-d 6) δ 11.28 (br s, 1H), 8.98 (s, 1H), 8.75 (br s, 1H), 8.43 (dd, J = 4.9, 1.5 Hz, 1H), 7.26 (dd, J = 5.1, 1.5 Hz, 1H), 6.99 (t, J = 8.1 Hz, 1H), 6.87 - 6.78 (m, 2H), 6.47 (ddd, J = 8.3, 2.2, 0.9 Hz, 1H).
    • Example 83: N-(4-Fluoro-3-(trifluoromethyl)phenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0289
  • N-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide was synthesized analogously to Example 80 using 4-fluoro-3-(trifluoromethyl)aniline in place of 3-bromoaniline. C14H8F4N4O. 325.0 [M+1]+.
    Figure imgb0290
  • N-(4-fluoro-3-(trifluoromethyl)phenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide. Example 83 was synthesized analogously to Example 80, using N-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide in place of N-(3-bromophenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide. C14H9F4N5O. 340.1 [M+1]+. 1H NMR (400 MHz, DMSO-d6 ) δ 11.18 (br s, 1H), 9.09 (s, 1H), 8.55 (br s, 1H), 8.40 (dd, J = 5.0, 1.8 Hz, 1H), 7.29 (d, J = 5.0 Hz, 1H), 7.16 - 7.07 (m, 2H), 6.85 - 6.79 (m, 1H).
    • Example 84: N-(4-Fluoro-3-(prop-1-yn-1-yl)phenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0291
  • 4-fluoro-3-(prop-1-yn-1-yl)aniline. A solution of 3-bromo-4-fluoroaniline (0.254 g, 1.337 mmol) and trimethyl(prop-1-yn-1-yl)silane (0.59 mL, 4.010 mmol) in DMF (1.5 mL) was degassed by bubbling N2 for approx. 5 min. CuI (0.025 g, 0.134 mmol), Pd(PPh3)2Cl2 (0.094 g, 0.134 mmol) and TBAF (4.68 mL of a 1 M solution in THF, 4.68 mmol) were added and the mixture was heated at 65 °C for 16 h. The mixture was diluted with water and extracted 3× with DCM. The combined organic layers were washed with sat. bicarb solution and brine, dried (Na2SO4), filtered and concentrated. The residue was purified via flash chromatography on silica gel to yield the desired product. C9H8FN. 150.0 [M+1]+.
    Figure imgb0292
  • N-(4-fluoro-3-(prop-1-yn-1-yl)phenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide. To a solution of 1H-imidazo[4,5-b]pyridine-7-carboxylic acid (0.030 g, 0.184 mmol), 4-fluoro-3-(prop-1-yn-1-yl)aniline (0.028 g, 0.134 mmol), HOBt (0.030 g, 0.221 mmol) and DIEA (0.08 mL, 0.46 mmol) in DMF (2 mL) was added EDC (0.05 mL, 0.22 mmol). The mixture stirred at room temperature for 16 h. The mixture was diluted with sat. bicarb solution and was extracted 3× with EtOAc. The combined organic layers were washed with 10% citric acid solution and brine, dried (Na2SO4), filtered, concentrated onto silica gel, and purified via flash chromatography on silica gel to yield the desired product. C16H11FN4O. 295.1 [M+1]+.
    Figure imgb0293
  • N-(4-fluoro-3-(prop-1-yn-1-yl)phenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide. Example 84 was synthesized analogously to Example 80, using N-(4-fluoro-3-(prop-1-yn-1-yl)phenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide in place of N-(3-bromophenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide. C16H12FN5O. 310.1 [M+1]+. 1H NMR (400 MHz, DMSO-d6 ) δ 11.02 (br s, 1H), 8.75 (s, 1H), 8.60 (brs, 1H), 8.36 (d, J = 4.9 Hz, 1H), 7.18 (d, J = 5.0 Hz, 1H), 6.85 (t, J = 9.1 Hz, 1H), 6.78 (dd, J = 6.3, 2.8 Hz, 1H), 6.52 (ddd, J = 8.
    8, 4.4, 2.9 Hz, 1H), 1.98 (s, 3H).
    • Example 85: N-(3-Bromo-4-chlorophenyl)-N-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0294
  • N-(3-bromo-4-chlorophenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide was synthesized analogously to Example 80, using 3-bromo-4-chloroaniline in place of 4-fluoro-3-(prop-1-yn-1-yl)aniline. C13H8BrClN4O. 350.9/352.9 [M+1]+.
    Figure imgb0295
  • N-(3-bromo-4-chlorophenyl)-N-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide. Example 85 was synthesized analogously to Example 80 using N-(3-bromo-4-chlorophenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide in place of N-(3-bromophenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide. C13H9BrClN5O. 366.0/368.0 [M+1]+. 1H NMR (400 MHz, DMSO-d6 ) δ 11.27 (br s, 1H), 9.01 (s, 1H), 8.65 (br s, 1H), 8.40 (dd, J = 5.1, 1.7 Hz, 1H), 7.25 (dd, J = 5.0, 1.5 Hz, 1H), 7.17 (d, J = 8.7 Hz, 1H), 7.11 (dd, J = 2.7, 0.8 Hz, 1H), 6.49 (dd, J = 8.7, 2.6 Hz, 1H).
    • Example 86: N-(3,4-Dichlorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0296
  • N-(3,4-dichlorophenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide. Example 86 was synthesized analogously to Example 80, using 3,4-dichloroaniline in place of 3-bromoaniline. C13H8Cl2N4O. 307.0 [M+1]+.
    Figure imgb0297
  • N-(3,4-dichlorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide. Example 86 was synthesized analogously to Example 80, using N-(3,4-dichlorophenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide in place of N-(3-bromophenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide. C13H9Cl2N50. 322.0 [M+1]+. 1H NMR (400 MHz, DMSO-d6 ) δ 11.33 (br s, 1H), 9.09 (s, 1H), 8.71 (br s, 1H), 8.44 (dd, J = 5.2, 1.8 Hz, 1H), 7.29 (dd, J = 5.0, 1.6 Hz, 1H), 7.21 (d, J = 8.7 Hz, 1H), 7.00 (d, J = 2.7 Hz, 1H), 6.49 (dd, J = 8.8, 2.6 Hz, 1H).
    • Example 87: N-(4-Chlorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0298
  • N-(4-chlorophenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide. To a solution of 1H-imidazo[4,5-b]pyridine-7-carboxylic acid (0.110 g, 0.674 mmol), 4-chloroaniline (0.088 g, 0.689 mmol), HOBt (0.109 g, 0.807 mmol) and DIEA (0.30 mL, 1.72 mmol) in DMF (3 mL) was added EDC (0.18 mL, 0.809 mmol). The mixture stirred at room temperature for 16 h. The mixture was diluted with sat. bicarb solution and the solid was isolated via filtration. The solid was suspended in approx. 3 mL THF. The solid was removed via filtration and the filter cake was washed with THF. The filtrate was dried (Na2SO4), filtered and concentrated under reduced pressure to yield the desired product. C13H9ClN4O. 273.0 [M+1]+.
    Figure imgb0299
  • N-(4-chlorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide. Example 87 was synthesized analogously to Example 80, using N-(4-chlorophenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide in place of N-(3-bromophenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide. C13H10ClN5O. 288.0 [M+1]+. 1H NMR (400 MHz, DMSO-d6 ) δ 11.19 (br s, 1H), 8.92 (s, 1H), 8.75 (br s, 1H), 8.41 (d, J = 5.1 Hz, 1H), 7.21 (d, J = 5.1 Hz, 1H), 7.07 (d, J = 8.8 Hz, 2H), 6.68 (d, J = 8.8 Hz, 2H).
    • Example 88: N-(4-Bromophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0300
  • N-(4-bromophenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide was synthesized analogously to Example 80, using 4-bromoaniline in place of 3-bromoaniline. C13H9BrN4O. 339.0/341.0 [M+23]+.
    Figure imgb0301
  • N-(4-bromophenyl)-N-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide. Example 88 was synthesized analogously to Example 80, using N-(4-bromophenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide in place of N-(3-bromophenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide. C13H10BrN5O. 332.0/334.0 [M+1]+. 1H NMR (400 MHz, DMSO-d6 ) δ 11.19 (br s, 1H), 8.89 (s, 1H), 8.72 (br s, 1H), 8.41 (d, J = 5.0 Hz, 1H), 7.21 (d, J = 5.3 Hz, 1H), 7.19 (d, J = 8.7 Hz, 2H), 6.62 (d, J = 8.8 Hz, 2H).
    • Example 89: N-(4-Fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0302
  • N-(4-fluorophenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide was synthesized analogously to Example 80 using 5-fluoroaniline in place of 3-bromoaniline. C13H9FN4O. 257.0 [M+1]+.
    Figure imgb0303
  • N-(4-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide. Example 89 was synthesized analogously to Example 80, using N-(4-fluorophenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide in place of N-(3-bromophenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide. C13H10FN5O. 272.1 [M+1]+. 1H NMR (400 MHz, DMSO-d6 ) δ 11.05 (br s, 1H), 8.80 (s, 1H), 8.72 (br s, 1H), 8.39 (dd, J = 5.1, 1.3 Hz, 1H), 7.18 (d, J = 5.1 Hz, 1H), 6.88 (t, J = 8.8 Hz, 2H), 6.71 (dd, J = 9.0, 4.8 Hz, 2H).
    • Example 90: N-(3-Cyano-4-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0304
  • N-(3-cyano-4-fluorophenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide was synthesized analogously to Example 80, using 3-cyano-4-fluoroaniline in place of 3-bromoaniline. C14H8FN5O. 282.0 [M+1]+.
    Figure imgb0305
  • N-(3-cyano-4-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide. Example 90 was synthesized analogously to Example 80, using N-(3-cyano-4-fluorophenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide in place of N-(3-bromophenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide. C14H9FN6O. 297.1 [M+1]+.
    • Example 91: N'-Hydroxy-N-(4-(trifluoromethyl)phenyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0306
  • N-(4-(trifluoromethyl)phenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide was synthesized analogously to Example 84, using 4-(trifluoromethyl)aniline in place of 4-fluoro-3-(prop-1-yn-1-yl)aniline. C14H9F3N4O. 307.0 [M+1]+.
    Figure imgb0307
  • N'-hydroxy-N-(4-(trifluoromethyl)phenyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide. Example 91 was synthesized analogously to Example 80 using N-(4-(trifluoromethyl)phenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide in place of N-(3-bromophenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide. C14H10F3N5O. 322.1 [M+1]+.
    • Example 92: N'-Hydroxy-N-(3-methoxyphenyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0308
  • N-(3-methoxyphenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide was synthesized analogously to Example 80, using 3-methoxyaniline in place of 3-bromoaniline. C14H12N4O2. 269.1 [M+1]+.
    Figure imgb0309
  • N'-hydroxy-N-(3-methoxyphenyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide. Example 92 was synthesized analogously to Example 80, using N-(3-methoxyphenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide in place of N-(3-bromophenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide. C14H13N5O2. 284.1 [M+1]+.
    • Example 93: N-(4-Fluoro-3-isopropylphenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0310
  • N-(4-fluoro-3-isopropylphenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide was synthesized analogously to Example 80, using 4-fluoro-3-isopropylaniline in place of 3-bromoaniline. C16H15FN4O. 299.0 [M+1]+.
    Figure imgb0311
  • N-(4-fluoro-3-isopropylphenyl)-N-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide. Example 93 was synthesized analogously to Example 80, using N-(4-fluoro-3-isopropylphenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide in place of N-(3-bromophenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide. C16H16FN5O. 314.1 [M+1]+.
    • Example 94: N'-Hydroxy-N-(p-tolyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0312
  • N-(p-tolyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide was synthesized analogously to Example 84, using p-toluidine in place of 4-fluoro-3-(prop-1-yn-1-yl)aniline. C14H12N4O. 253.1 [M+1]+.
    Figure imgb0313
  • N'-hydroxy-N-(p-tolyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide. Example 94 was synthesized analogously to Example 80, using N-(p-tolyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide in place of N-(3-bromophenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide. C14H13N5O. 268.1 [M+1]+.
    • Example 95: N-(3-Ethynylphenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0314
  • N-(3-ethynylphenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide. A solution of 1H-imidazo[4,5-b]pyridine-7-carboxylic acid (100 mg, 0.613 mmol), bis(2-oxo-3-oxazolidinyl)phosphinic chloride (312mg, 1.23mmol) and diisopropylethylamine (0.534 mL, 3.06 mmol) in dichloromethane (10 mL). was stirred for 16hr. The reaction mixture was filtered and absorbed onto silica gel and purified by silica gel chromatography to give the desired product (140 mg). C15H10N4O. 263.1 (M+1).
    Figure imgb0315
  • N-(3-ethynylphenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide. A mixture of N-(3-ethynylphenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide (41 mg, 0.155 mmol), phosphorous pentachloride (48 mg, 0.233 mmol) in phosphoryl chloride (0.3mL) and 1,2-dichloroethane (0.3 mL) were stirred at 80 °C for 2 hr. The reaction mixture was concentrated and suspended in ethanol (2 mL) and to this mixture was added 50% hydroxylamine in water (0.265 mL, 4.33 mmol). The reaction mixture stirred for 1 hr and was concentrated. The residue was purified by preparative HPLC to give two products (Example 95 and Example 96). N-(3-ethynylphenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide. C15H11N5O. 278.07 (M+1) 1H NMR (400 MHz, DMSO-d 6) δ 11.23 (s, 1H), 8.90 (s, 1H), 8.78 (s, 1H), 8.43 (d, J = 5.1 Hz, 1H), 7.24 (d, J = 5.1 Hz, 1H), 7.00 (t, J = 8.1 Hz, 1H), 6.93 - 6.85 (m, 2H), 6.59 (ddd, J = 8.2, 2.3, 1.1 Hz, 1H), 4.07 (s, 1H).
    • Example 96: N-(3-Ethylphenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0316
  • N-(3-ethylphenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide was prepared as described in Example 95. C15H15N5O. 281.10 (M+1) 1H NMR (400 MHz, DMSO-d6 ) δ 11.09 (s, 1H), 8.74 (d, J = 15.8 Hz, 2H), 8.39 (d, J = 5.1 Hz, 1H), 7.19 (d, J = 5.1 Hz, 1H), 6.98 - 6.87 (m, 1H), 6.64 (ddd, J = 7.5, 1.6, 0.9 Hz, 1H), 6.55 - 6.43 (m, 2H), 2.34 (q, J = 7.6 Hz, 2H), 0.89 (t, J = 7.6 Hz, 3H).
    • Example 97: N-(3-Ethynyl-4-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0317
  • N-(3-ethynyl-4-fluorophenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide was made analogously to Example 95 using 3-ethynyl-4-fluoroaniline in place of 3-ethynylaniline. C15H9FN4O. 281.00 (M+1).
    Figure imgb0318
  • N-(3-ethynyl-4-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide. Example 97 was made analogously to Example 95 C15H10FN5O. 295.09 (M+1). 1H NMR (400 MHz, DMSO-d 6) δ 11.17 (s, 1H), 8.90 (s, 1H), 8.78 (s, 1H), 8.43 (d, J = 5.1 Hz, 1H), 7.26 (d, J = 5.1 Hz, 1H), 6.98 - 6.89 (m, 2H), 6.62 (ddd, J = 9.0, 4.4, 2.9 Hz, 1H), 4.39 (d, J = 0.6 Hz, 1H).
    • Example 98: N-(3-(Difluoromethyl)phenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0319
  • N-(3-(difluoromethyl)phenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide was made analogously to Example 95 using 3-(difluoromethyl)aniline in place of 3-ethynylaniline. C14H10F2N4O. 289.10 (M+1).
    Figure imgb0320
  • N-(3-(difluoromethyl)phenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide. Example 98 was made analogously to Example 95 using N-(3-(difluoromethyl)phenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide. C14H11F2N5O. 304.10 (M+1) 1H NMR (400 MHz, DMSO-d 6) δ, 12.51 (s, 1H), 11.17 (s, 1H), 8.92 (d, J = 25.4 Hz, 1H), 8.41 (s, 1H), 8.33 (d, J = 5. 0 Hz, 1H), 7.41-7.23 (m, 1H), 7.19 - 7.02 (m, 1H), 7.02 - 6.80 (m, 2H), 6.73 (d, J = 8.2 Hz, 1H).
    • Example 99: N-Hydroxy-N-(3-(trifluoromethoxy)phenyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0321
  • N-(3-(trifluoromethoxy)phenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide was made analogously to Example 95 using 3-(trifluoromethoxy)aniline in place of 3-ethynylaniline. C14H9F3N4O2. 323.07 (M+1)
    Figure imgb0322
  • N-hydroxy-N-(3-(trifluoromethoxy)phenyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide. Example 99 was made analogously to Example 95 using N-(3-(trifluoromethoxy)phenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide. C14H10F3N5O2. 338.10 (M+1). 1H NMR (400 MHz, DMSO-d 6) δ 9.54 (s, 1H), 9.22 (s, 1H), 8.58 (d, J = 5.3 Hz, 1H), 7.40 (d, J = 5.3 Hz, 1H), 7.12 (td, J = 8.1, 0.5 Hz, 1H), 6.74 (ddt, J = 8.2, 2.1, 1.0 Hz, 1H), 6.69-6.61 (m, 3H).
    • Example 100: N-Hydroxy-N-phenyl-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0323
  • N-phenyl-1H-imidazo[4,5-b]pyridine-7-carboxamide was made analogously to Example 95 using aniline in place of 3-ethynylaniline. C13H10N4O. 239.10 (M+1).
    Figure imgb0324
  • N-hydroxy-N-phenyl-1H-imidazo[4,5-b]pyridine-7-carboximidamide. Example 100 was made analogously to Example 95 using N-phenyl-1H-imidazo[4,5-b]pyridine-7-carboxamide. C13H11N5O. 254.10 1H NMR (400 MHz, DMSO-d 6) δ 12.51 (s, 1H), 11.01 (s, 1H), 8.63 (s, 1H), 8.40 (d, J = 1.1 Hz, 1H), 8.34 - 8.26 (m, 1H), 7.08 - 6.99 (m, 2H), 6.95 (dd, J = 8.5, 7.3 Hz, 1H), 6.82 - 6.76 (m, 1H), 6.73 - 6.58 (m, 2H).
    • Example 101: N-(4-Fluoro-3-(trifluoromethoxy)phenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0325
  • N-(4-fluoro-3-(trifluoromethoxy)phenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide was made analogously to Example 95 using 4-fluoro-3-(trifluoromethoxy)aniline in place of 3-ethynylaniline. C14H8F4N4O2. 341.06 (M+1).
    Figure imgb0326
  • N-(4-fluoro-3-(trifluoromethoxy)phenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide. Example 101 was made analogously to Example 95 using N-(4-fluoro-3-(trifluoromethoxy)phenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide. C14H9F4N5O2. 355.07 (M+1). 1H NMR (400 MHz, DMSO-d 6) δ 11.26 (s, 1H), 9.10 (s, 1H), 8.77 (s, 1H), 8.45 (d, J = 5.1 Hz, 1H), 7.30 (d, J = 5.1 Hz, 1H), 7.24-7.10 (m, 1H), 6.76 - 6.70 (m, 2H).
    • Example 102: N-Hydroxy-N-(naphthalen-2-yl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0327
  • N-(naphthalen-2-yl)-1H-imidazo[4,5-b]pyridine-7-carboxamide was made analogously to Example 95 using naphthalen-2-amine in place of 3-ethynylaniline. C17H12N4O. 289.10 (M+1).
    Figure imgb0328
  • N-Hydroxy-N-(naphthalen-2-yl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide (Example 102) and N-(3-chloronaphthalen-2-yl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide (Example 103) were made analogously to Example 95 using N-(naphthalen-2-yl)-1H-imidazo[4,5-b]pyridine-7-carboxamide give two products (N-hydroxy-N-(naphthalen-2-yl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide and N-(3-chloronaphthalen-2-yl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide). C17H13N5O. 304.11 (M+1) and C17H12ClN5O. 338.11(M+1).
    • Example 103: N-(3-Chloronaphthalen-2-yl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0329
  • N-(3-Chloronaphthalen-2-yl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide was prepared according to Example 102. C17H12ClN5O. 338.11(M+1).
    • Example 104: N'-hydroxy-N-(naphthalen-1-yl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0330
  • N-(naphthalen-1-yl)-1H-imidazo[4,5-b]pyridine-7-carboxamide was made analogously to Example 95 using naphthalen-1-amine in place of 3-ethynylaniline. C17H12N4O. 289.10 (M+1).
    Figure imgb0331
  • N'-hydroxy-N-(naphthalen-1-yl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide (Example 104) and N-(4-chloronaphthalen-1-yl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide (Example 105) were made analogously to Example 95 using N-(naphthalen-1-yl)-1H-imidazo[4,5-b]pyridine-7-carboxamide give two products (N'-hydroxy-N-(naphthalen-1-yl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide and N-(4-chloronaphthalen-1-yl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide). C17H13N5O. 304.11 (M+1)
    • Example 105: N-(4-Chloronaphthalen-1-yl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0332
  • N-(4-Chloronaphthalen-1-yl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide. Example 105 was made analogously to Example 104. C17H12ClN5O. 338.11(M+1).
    • Example 106: N-(4-Fluoro-3-methoxyphenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0333
  • N-(4-fluoro-3-methoxyphenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide was made analogously to Example 95 using 4-fluoro-3-methoxyanilinein place of 3-ethynylaniline. C14H11FN4O2. 286.09 (M+1).
    Figure imgb0334
  • N-(4-fluoro-3-methoxyphenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide. Example 106 was made analogously to Example 95 using 4-fluoro-3-methoxyphenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide. C14H12FN5O2. 302.10 (M+1).
    • Example 107: N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-methyl-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0335
  • 2-Chloro-3-nitroisonicotinic acid. To a solution of 2-chloro-4-methyl-3-nitropyridine (5.0 g, 29 mmol) in sulfuric acid (40 mL) was added potassium dichromate (11.3 g, 38.5 mmol) in portions over 20 min. The reaction was stirred at 60 °C overnight and poured onto ice. The water was washed with ethyl acetate three times and the combined organic layers were dried over sodium sulfate, filtered and concentrated to give the desired product. C6H3ClN2O4. 203.1 (M+1).
    Figure imgb0336
  • 2-Chloro-N-(3-chloro-4-fluorophenyl)-3-nitroisonicotinamide. To a solution of 3-chloro-4-fluoroaniline (3.84 g, 26.4 mmol), 2-chloro-3-nitroisonicotinic acid (5.34 g, 26.4 mmol) and triethylamine (11 mL, 79 mmol) in dichlromethane (100 mL) in an ice bath was added phosphoryl chloride (3.69 mL, 39.6 mmol). The ice bath was removed and the reaction stirred for 1 hr. Saturated sodium bicarbonate was added and the aqueous layer was washed three times with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered and concentrated onto silica gel and purified by silica gel chromatography (0->100% ethyl acetate in dichloromethane) to give the desired product. C12H6C12FN3O3. 330.0 (M+1).
    Figure imgb0337
  • 2-Amino-N-(3-chloro-4-fluorophenyl)-3-nitroisonicotinamide. A mixture of 2-chloro-N-(3-chloro-4-fluorophenyl)-3-nitroisonicotinamide (4.78 g, 14.5 mmol) in ethanol (15 mL) and 28% ammonium hydroxide in water (14.1 mL, 101.4 mmol) was stirred in a closed vessel at 90 °C for 1.5 hr. The reaction mixture was cooled in an ice bath and the resulting precipitate filtered and washed with cold ethanol. Dried the solid on high vac to give desired product. C12H8ClFN4O3. 311.1 (M+1).
    Figure imgb0338
  • 2,3-Diamino-N-(3-chloro-4-fluorophenyl)isonicotinamide. A mixture of 2-amino-N-(3-chloro-4-fluorophenyl)-3-nitroisonicotinamide (3.43 g, 11.0 mmol) and 10 % Palladium on carbon (250 mg) in methanol (100 mL) was mixed in a Parr shaker at 40 psi hydrogen for 2 hr. Reaction was filtered and concentrated to give the desired product. C12H10ClFN4O. 281.1 (M+1).
    Figure imgb0339
  • N-(3-Chloro-4-fluorophenyl)-2-methyl-1H-imidazo[4,5-b]pyridine-7-carboxamide. A mixture of 2,3-diamino-N-(3-chloro-4-fluorophenyl)isonicotinamide (1.06 g, 3.77 mmol) in acetic acid (11 mL) was stirred at 180 °C for 1 hr in a microwave. Water was added and the resulting precipitate was filtered and dried on high vac to give the desired product. C14H10ClFN4O. 305.1 (M+1).
    Figure imgb0340
  • N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-methyl-1H-imidazo[4,5-b]pyridine-7-carboximidamide. A mixture of N-(3-Chloro-4-fluorophenyl)-2-methyl-1H-imidazo[4,5-b]pyridine-7-carboxamide (132 mg, 0.433 mmol), phosphorous pentachloride (135 mg, 0.650 mmol) in phosphoryl chloride (2 mL) and 1,2-dichloroethane (2 mL) were stirred at 80 °C for 2.5 hr. The reaction mixture was concentrated and suspended in ethanol (2 mL) and to this mixture was added 50% hydroxylamine in water (0.265 mL, 4.33 mmol). The reaction mixture stirred for 1 hr and was concentrated. The residue was purified by preparative HPLC to give the desired product. C14H11ClFN5O. 320.0 (M+1).
    • Example 108: N-(3-Chloro-4-fluorophenyl)-2-ethyl-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0341
  • N-(3-chloro-4-fluorophenyl)-2-ethyl-1H-imidazo[4,5-b]pyridine-7-carboxamide was made analogously to Example 107 using propionic acid in place of acetic acid. C15H12ClFN4O. 319.1 (M+1).
    Figure imgb0342
  • N-(3-chloro-4-fluorophenyl)-2-ethyl-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide. Example 108 was made analogously to Example 107 using N-(3-chloro-4-fluorophenyl)-2-ethyl-1H-imidazo[4,5-b]pyridine-7-carboxamide in place of N-(3-Chloro-4-fluorophenyl)-2-methyl-1H-imidazo[4,5-b]pyridine-7-carboxamide. C15H13ClFN5O. 334.1 (M+1).
    • Example 109: N-(3-Chloro-4-fluorophenyl)-2-cyclopropyl-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0343
  • N-(3-chloro-4-fluorophenyl)-2-cyclopropyl-1H-imidazo[4,5-b]pyridine-7-carboxamide was made analogously to Example 107 using cyclopropanecarboxylic acid in place of acetic acid. C16H12ClFN4O. 331.1 (M+1).
    Figure imgb0344
  • N-(3-chloro-4-fluorophenyl)-2-cyclopropyl-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide. Example 109 was made analogously to Example 107 using N-(3-chloro-4-fluorophenyl)-2-cyclopropyl-1H-imidazo[4,5-b]pyridine-7-carboxamide in place of N-(3-Chloro-4-fluorophenyl)-2-methyl-1H-imidazo[4,5-b]pyridine-7-carboxamide. C16H13ClFN5O. 346.1 (M+1).
    • Example 110: N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-(methoxymethyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0345
  • N-(3-chloro-4-fluorophenyl)-2-(methoxymethyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide was made analogously to Example 107 using methoxyacetic acid in place of acetic acid. C15H12ClFN4O2. 334.9 (M+1).
    Figure imgb0346
  • 4-(3-chloro-4-fluorophenyl)-3-(2-(methoxymethyl)-1H-imidazo[4,5-b]pyridin-7-yl)-1,2,4-oxadiazol-5(4H)-one. A mixture of N-(3-chloro-4-fluorophenyl)-2-(methoxymethyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide (2.62 g, 7.82 mmol), phosphorous pentachloride (2.44 g, 11.7 mmol) in phosphoryl chloride (22 mL) and 1,2-dichloroethane (22 mL) were stirred at 80 °C for 2.5 hr. The reaction mixture was concentrated and suspended in ethanol (20 mL) and to this mixture was added 50% hydroxylamine in water (4.8 mL, 78 mmol). The reaction mixture stirred for 1 hr and was concentrated. Water and aqueous saturated sodium bicarbonate were added and the solid was filtered and dried on high vac. The solid was suspended in ethyl acetate (100 mL) and to this mixture was added carbonyldiimidazole (1.90 g, 11.7 mmol). The mixture was stirred for 18 hr and concentrated. The residue was purified by silica gel chromatography to give the desired product (871 mg). C16H11ClFN5O3. 376.3 (M+1).
    Figure imgb0347
  • N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(methoxymethyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide. Example 110 was made analogously to Example 95 using N-(3-chloro-4-fluorophenyl)-2-(methoxymethyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide. C15H13ClFN5O2. 350.1 (M+1).
    • Example 111: 4-(3-Chloro-4-fluorophenyl)-3-(2-(hydroxymethyl)-1H-imidazo [4,5-b]pyridin-7-yl)-1,2,4-oxadiazol-5(4H)-one
  • Figure imgb0348
  • To a mixture of 4-(3-chloro-4-fluorophenyl)-3-(2-(methoxymethyl)-1H-imidazo[4,5-b]pyridin-7-yl)-1,2,4-oxadiazol-5(4H)-one (400 mg, 1.07 mmol) in dichloromethane (8 mL) at 0 °C was added a solution of 1 M boron tribromide in dichloromethane (1.60 mL, 1.60 mmol). The reaction was allowed to warm to room temperature and stirred for 18 hr. The reaction mixture was diluted with dichloromethane and saturated sodium bicarbonate and the aqueous layer was washed three times with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered, loaded onto silica gel column and purified by silica gel chromatography to give two product: 4-(3-chloro-4-fluorophenyl)-3-(2-(hydroxymethyl)-1H-imidazo[4,5-b]pyridin-7-yl)-1,2,4-oxadiazol-5(4H)-one (385 mg) and 3-(2-(bromomethyl)-1H-imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one. C15H9ClFN5O3. 362.0 (M+1).
    Figure imgb0349
  • 3-(2-(bromomethyl)-1H-imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one. C15H8BrClFN5O2. 425.9 (M+1).
    • Example 112: N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-(morpholinomethyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0350
  • (7-(4-(3-chloro-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-1-(methylsulfonyl)-1H-imidazo[4,5-b]pyridin-2-yl)methyl methanesulfonate. To a solution of 4-(3-chloro-4-fluorophenyl)-3-(2-(hydroxymethyl)-1H-imidazo[4,5-b]pyridin-7-yl)-1,2,4-oxadiazol-5(4H)-one (510 mg, 1.41 mmol) and triethylamine (1.97 mL, 14.1 mmol) in dichlromethane (20 mL) at -78 °C was added methanesulfonyl chloride (0.548 mL, 7.05 mmol) dropwise over 10 min. The reaction mixture was warmed to 0 °C and stirred for 10 min. Water was added and the aqueous layer was washed three times with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography to give two product: (7-(4-(3-chloro-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-1-(methylsulfonyl)-1H-imidazo[4,5-b]pyridin-2-yl)methyl methanesulfonate (440 mg) and 4-(3-chloro-4-fluorophenyl)-3-(2-(chloromethyl)-1-(methylsulfonyl)-1H-imidazo[4,5-b]pyridin-7-yl)-1,2,4-oxadiazol-5(4H)-one. C17H13ClFN5O7S2. 518.2 (M+1).
    Figure imgb0351
  • 4-(3-chloro-4-fluorophenyl)-3-(2-(chloromethyl)-1-(methylsulfonyl)-1H-imidazo[4,5-b]pyridin-7-yl)-1,2,4-oxadiazol-5(4H)-one was prepared from the above reaction. C16H10Cl2FN5O4S. 458.0 (M+1).
    Figure imgb0352
  • N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(morpholinomethyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide. A solution of (7-(4-(3-chloro-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-1-(methylsulfonyl)-1H-imidazo[4,5-b]pyridin-2-yl)methyl methanesulfonate (27 mg, 0.052 mmol) and morpholine (0.10 mL, 1.1 mmol) in acetonitrile (1 mL) was stirred at 65 °C for 10 min. The reaction was concentrated. The residue was brought up in tetrahydrofuran (0.5 mL) and water (0.5 mL). To this solution was added 2 N sodium hydroxide (0.39 mL, 0.78 mmol) and the reaction mixture stirred for 10 min. To the mixture was added acetic acid (0.05 mL) and the solution was loaded directly onto a prep HPLC for purification to give the desired product. C18H18ClFN6O2. 405.1 (M+1).
    • Example 113: N-(3-Chloro-4-fluorophenyl)-2-((dimethylamino)methyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0353
  • N-(3-chloro-4-fluorophenyl)-2-((dimethylamino)methyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide. A solution of 4-(3-chloro-4-fluorophenyl)-3-(2-(chloromethyl)-1-(methylsulfonyl)-1H-imidazo[4,5-b]pyridin-7-yl)-1,2,4-oxadiazol-5(4H)-one (30 mg, 0.065 mmol) and dimethylamine (2 M in THF, 0.655 mL, 1.3 mmol) in acetonitrile (1 mL) was stirred at 65 °C for 3 hr min. The reaction was concentrated. The residue was brought up in tetrahydrofuran (0.5 mL) and water (0.5 mL). To this solution was added 2 N sodium hydroxide (0.39 mL, 0.78 mmol) and the reaction mixture stirred for 10 min. To the mixture was added acetic acid (0.05 mL) and the solution was loaded directly onto a prep HPLC for purification to give the desired product (12 mg). C16H16ClFN6O. 363.1 (M+1).
    • Example 114: N-(3-Chloro-4-fluorophenyl)-2-((ethylamino)methyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0354
  • N-(3-chloro-4-fluorophenyl)-2-((ethylamino)methyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide. Example 114 was made analogously to Example 112 using 2 M ethylamine in THF in place of morpholine. C16H16ClFN6O. 363.1 (M+1). 1H NMR (400 MHz, DMSO-d6 ) δ 12.76 (s, 1H), 11.16 (s, 1H), 9.29 (s, 2H), 8.96 (s, 1H), 8.38 (d, J = 5.0 Hz, 1H), 7.41 - 6.99 (m, 2H), 6.92 (dd, J = 6.5, 2.7 Hz, 1H), 6.51 (d, J = 8.7 Hz, 1H), 4.47 (s, 2H), 3.08 (s, 2H), 1.23 (t, J = 7.3 Hz, 3H).
    • Example 115: 2-((Benzylamino)methyl)-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0355
  • 2-((benzylamino)methyl)-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide. Example 115 was made analogously to Example 112 using benzylamine in place of morpholine. C21H18ClFN6O. 425.1 (M+1).
    • Example 116: N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-((isopropylamino)methyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0356
  • N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((isopropylamino)methyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide. Example 116 was made analogously to Example 112 using isopropylamine in place of morpholine. C17H18ClFN6O. 377.1 (M+1). 1H NMR (400 MHz, DMSO-d6 ) δ 11.18 (s, 1H), 9.28 (s, 2H), 8.96 (s, 1H), 8.38 (d, J = 5.0 Hz, 1H), 7.24 - 6.96 (m, 2H), 6.91 (dd, J = 6.5, 2.7 Hz, 1H), 6.51 (s, 1H), 4.48 (s, 2H), 3.56 - 3.28 (m, 1H), 1.37 - 1.15 (m, 6H).
    • Example 117: N-(3-Chloro-4-fluorophenyl)-2-(((cyclopropylmethyl)amino)methyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0357
  • N-(3-chloro-4-fluorophenyl)-2-(((cyclopropylmethyl)amino)methyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide. Example 117 was made analogously to Example 112 using cyclopropylmethylamine in place of morpholine. C18H18ClFN6O. 388.9 (M+1). 1H NMR (400 MHz, DMSO-d6 ) δ 11.14 (s, 1H), 9.41 (s, 2H), 8.95 (s, 1H), 8.38 (d, J = 5.0 Hz, 1H), 7.28 - 6.98 (m, 2H), 6.91 (dd, J = 6.5, 2.7 Hz, 1H), 6.52 (ddd, J = 9.0, 4.0, 2.8 Hz, 1H), 4.50 (s, 2H), 2.96 (s, 2H), 1.17 - 0.92 (m, 1H), 0.68 - 0.48 (m, 2H), 0.42 - 0.24 (m, 2H).
    • Example 118: N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-(((2,2,2-trifluoroethyl)amino)methyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0358
  • N-(3-chloro-4-fluorophenyl)-2-(((cyclopropylmethyl)amino)methyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide. Example 118 was made analogously to Example 112 using 2,2,2-trifluoroethylamine in place of morpholine. C16H13ClF4N6O. 416.7 (M+1).
    • Example 119: N-(3-Chloro-4-fluorophenyl)-2-((cyclopropylamino)methyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0359
  • N-(3-chloro-4-fluorophenyl)-2-((cyclopropylamino)methyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide. Example 119 was made analogously to Example 112 using cyclopropylamine in place of morpholine. C17H16ClFN6O. 374.9 (M+1).
    • Example 120: N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-(((3-methoxypropyl)amino)methyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0360
  • N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(((3-methoxypropyl)amino)methyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide. Example 120 was made analogously to Example 112 using 3-methoxypropylamine in place of morpholine. C18H20ClFN6O2. 407.1 (M+1).
    • Example 121: N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-(((pyridin-2-ylmethyl)amino)methyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0361
  • N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(((pyridin-2-ylmethyl)amino)methyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide. Example 121 was made analogously to Example 112 using pyridin-2-ylmethanamine in place of morpholine. C20H17ClFN7O. 426.1 (M+1).
    • Example 122: N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-(((3-methoxypropyl)(methyl)amino)methyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0362
  • N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(((3-methoxypropyl)(methyl)amino)methyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide. Example 122 was made analogously to Example 112 using 3-(2-(bromomethyl)-1H-imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one and 3-methoxy-N-methylpropan-1-amine in place of (7-(4-(3-chloro-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-1-(methylsulfonyl)-1H-imidazo[4,5-b]pyridin-2-yl)methyl methanesulfonate and morpholine. C19H22ClFN6O2. 421.2 (M+1).
    • Example 123: N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-(((2-methoxybenzyl)amino)methyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0363
  • N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(((2-methoxybenzyl)amino)methyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide. Example 123 was made analogously to Example 112 using 4-(3-chloro-4-fluorophenyl)-3-(2-(chloromethyl)-1-(methylsulfonyl)-1H-imidazo[4,5-b]pyridin-7-yl)-1,2,4-oxadiazol-5(4H)-one and 2-methoxybenzylamine in place of (7-(4-(3-chloro-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-1-(methylsulfonyl)-1H-imidazo[4,5-b]pyridin-2-yl)methyl methanesulfonate and morpholine. C22H20ClFN6O2. 455.1 (M+1).
    • Example 124: N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-(((2-methoxyethyl)amino)methyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0364
  • N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(((2-methoxyethyl)amino)methyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide. Example 124 was made analogously to Example 112 using 2-methoxyethylamine in place of morpholine.C17H18ClFN6O2. 393.1(M+1).
    • Example 125: N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-(((2-(pyridin-2-yl)ethyl)amino)methyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0365
  • N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(((2-(pyridin-2-yl)ethyl)amino)methyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide. Example 125 was made analogously to Example 112 using 2-(pyridin-2-yl)ethanamine in place of morpholine. C21H19ClFN7O. 440.1 (M+1).
    • Example 126: N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-(((pyridin-3-ylmethyl)amino)methyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0366
  • N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(((pyridin-3-ylmethyl)amino)methyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide. Example 126 was made analogously to Example 112 using 3-picolylamine in place of morpholine. C20H17ClFN7O. 426.1 (M+1).
    • Example 127: N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-((((tetrahydro-2H-pyran-2-yl)methyl)amino)methyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0367
  • N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((((tetrahydro-2H-pyran-2-yl)methyl)amino)methyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide. Example 127 was made analogously to Example 112 using 4-(3-chloro-4-fluorophenyl)-3-(2-(chloromethyl)-1-(methylsulfonyl)-1H-imidazo[4,5-b]pyridin-7-yl)-1,2,4-oxadiazol-5(4H)-one and (tetrahydro-2H-pyran-2-yl)methanamine in place of (7-(4-(3-chloro-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-1-(methylsulfonyl)-1H-imidazo[4,5-b]pyridin-2-yl)methyl methanesulfonate and morpholine. C20H22ClFN6O2. 433.1 (M+1).
    • Example 128: N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-((phenylamino)methyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0368
  • A solution of (7-(4-(3-chloro-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-1-(methylsulfonyl)-1H-imidazo[4,5-b]pyridin-2-yl)methyl methanesulfonate (14 mg, 0.027 mmol) and aniline (0.025 mL, 0.27 mmol) in acetonitrile (1 mL) was stirred at 65 °C for 18 hr. To the solution was added isopropylamine (0.1 mL) and the reaction stirred at 65 °C for 5 min. The reaction was concentrated. The residue was brought up in tetrahydrofuran (0.3 mL) and water (0.3 mL). To this solution was added 2 N sodium hydroxide (0.2 mL, 0.41 mmol) and the reaction mixture stirred for 10 min. To the mixture was added acetic acid (0.05 mL) and the solution was loaded directly onto a prep HPLC for purification to give the desired product. C20H16ClFN6O. 411.1 (M+1).
    • Example 129: N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-((((tetrahydro-2H-pyran-3-yl)methyl)amino)methyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0369
  • N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((((tetrahydro-2H-pyran-3-yl)methyl)amino)methyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide. Example 129 was made analogously to Example 112 using (tetrahydro-2H-pyran-3-yl)methanamine in place of morpholine. C20H22ClFN6O2. 433.1 (M+1).
    • Example 130: N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-(((pyrimidin-2-ylmethyl)amino)methyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0370
  • N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(((pyrimidin-2-ylmethyl)amino)methyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide. Example 130 was made analogously to Example 112 using pyrimidin-2-ylmethanamine in place of morpholine. C19H16ClFN8O. 427.1 (M+1).
    • Example 131: N-(3-Chloro-4-fluorophenyl)-N-hydroxy-2-(((3-morpholinopropyl)amino)methyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0371
  • Example 131 was made analogously to Example 112 using 3-morpholinopropan-1-amine in place of morpholine. C21H25ClFN7O2. 462.2 (M+1).
    • Example 132: N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-(((tetrahydro-2H-pyran-4-yl)amino)methyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0372
  • Example 132 was made analogously to Example 112 using 4-(3-chloro-4-fluorophenyl)-3-(2-(chloromethyl)-1-(methylsulfonyl)-1H-imidazo[4,5-b]pyridin-7-yl)-1,2,4-oxadiazol-5(4H)-one and tetrahydro-2H-pyran-4-amine in place of (7-(4-(3-chloro-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-1-(methylsulfonyl)-1H-imidazo[4,5-b]pyridin-2-yl)methyl methanesulfonate and morpholine. C19H20ClFN6O2. 419.1 (M+1).
    • Example 133: N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-(((pyridin-4-ylmethyl)amino)methyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0373
  • Example 133 was made analogously to Example 112 using 4-picolylamine in place of morpholine. C20H17ClFN7O. 426.1 (M+1).
    • Example 134: N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-(((pyrazin-2-ylmethyl)amino)methyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0374
  • Example 134 was made analogously to Example 112 using pyrazin-2-ylmethanamine in place of morpholine. C19H16ClFN8O. 427.1 (M+1).
    • Example 135: N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-((((tetrahydrofuran-3-yl)methyl)amino)methyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0375
  • Example 135 was made analogously to Example 112 using 4-(3-chloro-4-fluorophenyl)-3-(2-(chloromethyl)-1-(methylsulfonyl)-1H-imidazo[4,5-b]pyridin-7-yl)-1,2,4-oxadiazol-5(4H)-one and (tetrahydrofuran-3-yl)methanamine in place of (7-(4-(3-chloro-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-1-(methylsulfonyl)-1H-imidazo[4,5-b]pyridin-2-yl)methyl methanesulfonate and morpholine. C19H20ClFN6O2. 419.1 (M+1).
    • Example 136: N-(3-Chloro-4-fluorophenyl)-2-(((2-(dimethylamino)ethyl)amino)methyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0376
  • Example 136 was made analogously to Example 112 using N,N-dimethylethane-l,2-diamine in place of morpholine. C18H21ClFN7O. 406.1 (M+1).
    • Example 137: N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-(((2-(pyrimidin-2-yl)ethyl)amino)methyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0377
  • Example 137 was made analogously to Example 112 using 2-(pyrimidin-2-yl)ethanamine in place of morpholine. C20H18ClFN8O. 441.1 (M+1).
    • Example 138: N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-(((3-hydroxypropyl)amino)methyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0378
  • Example 138 was made analogously to Example 112 using 3-aminopropanol in place of morpholine. C17H18ClFN6O2. 393.1 (M+1).
    • Example 139: N-(3-Chloro-4-fluorophenyl)-N-hydroxy-2-(pyrrolidin-1-ylmethyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0379
  • Example 139 was synthesized analogously to Example 112 using pyrrolidine in place of morpholine. C18H18ClFN6O. 389.1 [M+1]+.
    • Example 140: N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-(piperidin-1-ylmethyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0380
  • Example 140 was synthesized analogously to Example 112 using piperidine in place of morpholine. C19H20ClFN6O. 403.1 [M+1]+.
    • Example 141: N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-((neopentylamino)methyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0381
  • Example 141 was synthesized analogously to Example 112 using 3-(2-(bromomethyl)-1H-imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one and 2,2-dimethylpropan-1-amine in place of (7-(4-(3-chloro-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-1-(methylsulfonyl)-1H-imidazo[4,5-b]pyridin-2-yl)methyl methanesulfonate and morpholine, respectively. C19H22ClFN6O. 405.2 [M+1]+.
    • Example 142: N-(3-Chloro-4-fluorophenyl)-2-(((2,2-difluoroethyl)amino)methyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0382
  • Example 142 was synthesized analogously to Example 112 using 3-(2-(bromomethyl)-1H-imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one and 2,2-difluoroethylamine in place of (7-(4-(3-chloro-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-1-(methylsulfonyl)-1H-imidazo[4,5-b]pyridin-2-yl)methyl methanesulfonate and morpholine, respectively. C16H14ClF3N6O. 399.1 [M+1]+.
    • Example 143: N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-(((3-hydroxy-2,2-dimethylpropyl)amino)methyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0383
  • Example 143 was synthesized analogously to Example 112 using 3-(2-(bromomethyl)-1H-imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one and 3-amino-2,2-dimethylpropan-1-ol in place of (7-(4-(3-chloro-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-1-(methylsulfonyl)-1H-imidazo[4,5-b]pyridin-2-yl)methyl methanesulfonate and morpholine, respectively. C19H22ClFN6O2. 421.2 [M+1]+.
    • Example 144: N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-(((thiazol-2-ylmethyl)amino)methyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0384
  • Example 144 was synthesized analogously to Example 112 using 3-(2-(bromomethyl)-1H-imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one and thiazol-2-ylmethanamine in place of (7-(4-(3-chloro-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-1-(methylsulfonyl)-1H-imidazo[4,5-b]pyridin-2-yl)methyl methanesulfonate and morpholine, respectively. C18H15ClFN7OS. 432.1 [M+1]+.
    • Example 145: N-((7-(N-(3-Chloro-4-fluorophenyl)-N'-hydroxycarbamimidoyl)-1H-imidazo[4,5-b]pyridin-2-yl)methyl)acetamide
  • Figure imgb0385
  • A solution of (7-(4-(3-chloro-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-1-(methylsulfonyl)-1H-imidazo[4,5-b]pyridin-2-yl)methyl methanesulfonate (17 mg, 0.033 mmol) and 0.5 M ammonia in dioxane (1.44 mL, 0.722 mmol) in acetonitrile (1 mL) was stirred at 65 °C for 30 min. The reaction was concentrated. The residue was brought up in tetrahydrofuran (0.5 mL) and to this solution was added triethylamine (0.021 mL, 0.15 mmol) and acetyl chloride (0.003 mL, 0.045 mmol. The reaction stirred for 3 hr and, then, more acetyl chloride (0.003 mL, 0.045 mmol) was added. The reaction stirred for 2 hr and was concentrated. The residue was brought up in tetrahydrofuran (0.3 mL) and water (0.3 mL). To this solution was added 2 N sodium hydroxide (0.22 mL, 0.44 mmol) and the reaction mixture stirred for 10 min. To the mixture was added acetic acid (0.05 mL) and the solution was loaded directly onto a prep HPLC for purification to give the desired product. C16H14ClFN6O2. 377.1 (M+1).
    • Example 146: N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-(thiophen-2-yl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0386
  • Methyl-2-(thiophen-2-yl)-1H-imidazo[4,5-b]pyridine. A solution of 4-methyl-3-nitropyridin-2-amine (400 mg, 2.61 mmol), thiophene-2-carbaldehyde (449 mg, 3.92 mmol) and sodium hydrosulfite (1.61 g, 7.84 mmol) in dimethyl sulfoxide (5 mL) and ethanol (5 mL) were stirred at 90 °C for 18 hr. The mixture was allowed to cool to room temperature and to this mixture was added water and the aqueous layer was washed three times with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, absorbed onto silica gel and purified by silica gel chromatography to give the desired product. C11H9N3S. 216.1 (M+1).
    Figure imgb0387
  • Methyl 2-(thiophen-2-yl)-1H-imidazo[4,5-b]pyridine-7-carboxylate. A solution of 7-methyl-2-(thiophen-2-yl)-1H-imidazo[4,5-b]pyridine (234 mg, 1.09 mmol) and selenium dioxide (482, 4.35 mmol) in pyridine (2.5 mL) was stirred at 120 °C for 24 hours. The reaction mixture was filtered through a pad of celite and the celite pad was washed with hot water and methanol. The filtrate was concentrated and the resulting residue was dried on high vac. The residue was brought up in methanol (10 mL) and to this solution was added thionyl chloride (0.55 mL, 7.6 mmol). The solution was stirred at 70 °C for 4 hours. The resulting mixture was concentrated to give the desired product. C12H9N3O2S. 260.1 (M+1).
    Figure imgb0388
  • N-(3-chloro-4-fluorophenyl)-2-(thiophen-2-yl)-1H-imidazo[4,5-b]pyridine-7-carboxamide. To a soln of the 3-chloro-4-fluoroanilinein (239 mg, 1.64 mmol) dichloroethane at 0 °C under nitrogen was added trimethylaluminum (2 M in heptane, 1.57, 3.15 mmol) dropwise over 5 min. The solution was allowed to warm to room temperature and stirred for 30 min. The solution was cooled to 0 °C and to this solution was added methyl 2-(thiophen-2-yl)-1H-imidazo[4,5-b]pyridine-7-carboxylate (272 mg, 1.05 mmol). The solution was stirred at 85 °C for 18 hr and, then, cooled to room temperature. Saturated sodium bicarbonate was carefully added to the solution and the aqueous layer was washed three times with dichloromethane. The aqueous layer was acidified with 10% citric acid and the resulting precipitate was filtered and dried on high vac to give the desired product. C17H10ClFN4OS. 373.1 (M+1).
    Figure imgb0389
  • N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(thiophen-2-yl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide. Example 146 was made analogously to Example 107 using N-(3-chloro-4-fluorophenyl)-2-(thiophen-2-yl)-1H-imidazo[4,5-b]pyridine-7-carboxamide in place of N-(3-Chloro-4-fluorophenyl)-2-methyl-1H-imidazo[4,5-b]pyridine-7-carboxamide. C17H11ClFN5OS. 388.1 (M+1).
    • Example 147: N-(3-Chloro-4-fluorophenyl)-N-hydroxy-2-(pyridin-3-yl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0390
  • N-(3-chloro-4-fluorophenyl)-2-(pyridin-3-yl)-1H-imidazo[4,5-b]pyridine-7-carboxamide. A mixture of 2,3-diamino-N-(3-chloro-4-fluorophenyl)isonicotinamide (0.150 g, 0.534 mmol) and nicotinaldehyde (0.50 mL, 5.34 mmol) in DMSO was stirred at 100 °C under air atmosphere for 16 h. Mixture was cooled to rt and diluted with water. The aqueous layer was extracted 3 × with EtOAc and the combined organic layers were washed with brine, dried (Na2SO4), filtered, concentrated onto silica gel, and purified via column chromatography on silica gel to yield the final product. C18H11ClFN5O. 368.1 [M+1]+.
    Figure imgb0391
  • Example 147 was synthesized analogously to Example 80, using N-(3-chloro-4-fluorophenyl)-2-(pyridin-3-yl)-1H-imidazo[4,5-b]pyridine-7-carboxamide in place of N-(3-bromophenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide. C18H12ClFN6O. 383.1 [M+1]+.
    • Example 148: N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-(1H-pyrrol-2-yl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0392
  • N-(3-chloro-4-fluorophenyl)-2-(1H-pyrrol-2-yl)-1H-imidazo[4,5-b]pyridine-7-carboxamide was synthesized analogously to Example 147 using 1H-pyrrole-2-carbaldehyde in place of nicotinaldehyde. C17H11ClFN5O. 356.1 [M+1]+.
    Figure imgb0393
  • Example 148 was synthesized analogously to Example 80, using N-(3-chloro-4-fluorophenyl)-2-(1H-pyrrol-2-yl)-1H-imidazo[4,5-b]pyridine-7-carboxamide in place of N-(3-bromophenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide. C17H12ClFN6O. 371.1 [M+1]+.
    • Example 149: N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-(1H-imidazol-2-yl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0394
  • Methyl 2,3-diaminoisonicotinate. A mixture of 2,3-diaminoisonicotinic acid (2.0 g, 13 mmol) in sulfuric acid (2.5 mL) and methanol (25 mL) was stirred at 120 °C in a microwave for 1 hr. To the reaction mixture was added aqueous saturated sodium bicarbonate until basic and the aqueous layer was washed three times with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated to give the desired product. C7H9N3O2. 168.1 (M+1).
    Figure imgb0395
  • Methyl 2-(1H-imidazol-2-yl)-1H-imidazo[4,5-b]pyridine-7-carboxylate was made analogously to Example 147 using methyl 2,3-diaminoisonicotinate and 1H-imidazole-2-carbaldehyde. C11H9N5O2. 244.0 (M+1).
    Figure imgb0396
  • N-(3-chloro-4-fluorophenyl)-2-(1H-imidazol-2-yl)-1H-imidazo[4,5-b]pyridine-7-carboxamide was made analogously to Example 146 using methyl 2-(1H-imidazol-2-yl)-1H-imidazo[4,5-b]pyridine-7-carboxylate in place of methyl 2-(thiophen-2-yl)-1H-imidazo[4,5-b]pyridine-7-carboxylate. C16H10ClFN6O. 357.2 (M+1).
    Figure imgb0397
  • Example 149 was made analogously to Example 107 using N-(3-chloro-4-fluorophenyl)-2-(1H-imidazol-2-yl)-1H-imidazo[4,5-b]pyridine-7-carboxamide in place of N-(3-Chloro-4-fluorophenyl)-2-methyl-1H-imidazo[4,5-b]pyridine-7-carboxamide. C16H11ClFN7O. 372.1 (M+1). 1H NMR (400 MHz, DMSO-d6 ) δ 11.07 (s, 1H), 8.92 (s, 1H), 8.33 (d, J = 5.1 Hz, 1H), 7.44 (s, 2H), 7.18 (d, J = 5.1 Hz, 1H), 7.02 (t, J = 9.1 Hz, 1H), 6.96 (dd, J = 6.5, 2.7 Hz, 1H), 6.56 (ddd, J = 9.0, 4.1, 2.7 Hz, 1H).
    • Example 150: N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-(1H-pyrazol-5-yl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0398
  • N-(3-chloro-4-fluorophenyl)-2-(1H-pyrazol-5-yl)-1H-imidazo[4,5-b]pyridine-7-carboxamide was synthesized analogously to Example 147 using 1H-pyrazole-5-carbaldehyde in place of nicotinaldehyde. C16H10ClFN6O. 357.1 [M+1]+.
    Figure imgb0399
  • N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(1H-pyrazol-5-yl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide. Example 150 was synthesized analogously to Example 80, using N-(3-chloro-4-fluorophenyl)-2-(1H-pyrazol-5-yl)-1H-imidazo[4,5-b]pyridine-7-carboxamide in place of N-(3-bromophenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide. C16H11ClFN7O. 372.1 [M+1]+.
    • Example 151: N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-(4-methyl-1H-imidazol-2-yl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0400
  • Methyl 2-(4-methyl-1H-imidazol-2-yl)-1H-imidazo[4,5-b]pyridine-7-carboxylate. A mixture of methyl 2,3-diaminoisonicotinate (0.102 g, 0.610 mmol) and 4-methyl-1H-imidazole-2-carbaldehyde (0.319 g, 2.90 mmol) in DMSO (5 mL) stirred at 100 °C under air atmosphere for 16 h. The mixture was diluted with water and the solid was isolated via filtration. The filter cake was washed with water and then cooled over dry ice and dried on the lyophilizer to give the desired product, which was taken on without purification. C12H11N5O2. 258.1 [M+1]+.
    Figure imgb0401
  • N-(3-chloro-4-fluorophenyl)-2-(4-methyl-1H-imidazol-2-yl)-1H-imidazo[4,5-b]pyridine-7-carboxamide. To DABAL-Me3 (0.128 g, 0.499 mmol) in THF (2 mL) was added 3-chloro-4-fluoroaniline (0.073 g, 0.499 mmol). The mixture stirred at 40 °C for 1 h. A slurry of methyl 2-(4-methyl-1H-imidazol-2-yl)-1H-imidazo[4,5-b]pyridine-7-carboxylate (0.080 g, 0.311 mmol) in THF (2.5 mL) was added and the mixture stirred at 65 °C for 16 h. The mixture was quenched by the addition of 1 N HCl (1 mL) and then was diluted with water/EtOAc. The aqueous layer was extracted 3× with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4), filtered, concentrated onto silica gel, and purified via column chromatography on silica gel to yield the desired product. C17H12ClFN6O. 371.1 [M+1]+.
    Figure imgb0402
  • N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(4-methyl-1H-imidazol-2-yl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide. To a mixture of N-(3-chloro-4-fluorophenyl)-2-(4-methyl-1H-imidazol-2-yl)-1H-imidazo[4,5-b]pyridine-7-carboxamide (0.009 g, 0.024 mmol) in DCE (0.5 mL) and phosphoryl chloride (0.5 mL) was added phosphorus pentachloride (0.008 g, 0.036 mmol). The mixture stirred at 90 °C for 4 h. Additional phosphorus pentachloride (0.008 g, 0.036 mmol) was added and the mixture stirred at 90 °C for 72 h. The mixture was cooled to rt and concentrated. The residue was diluted with EtOH (3 mL) and hydroxylamine (0.05 mL of a 50 w/w% solution in water, 0.82 mmol) was added. The mixture was concentrated and the residue was diluted with DMSO/water and purified via preparative HPLC to yield the desired product. C17H13ClFN7O. 386.0 [M+1]+.
    • Example 152: N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-(pyrrolidin-2-yl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0403
  • (S)-tert-butyl 2-((2-amino-4-((3-chloro-4-fluorophenyl)carbamoyl)pyridin-3-yl)carbamoyl)pyrrolidine-1-carboxylate. To N-Boc-L-proline (0.429 g, 1.991 mmol) in DCM (20 mL) at 0 °C was added isobutyl chloroformate (0.57 mL, 4.38 mmol) dropwise, followed by TEA (0.69 mL, 4.98 mmol). 2,3-diamino-N-(3-chloro-4-fluorophenyl)isonicotinamide (0.559 g, 1.991 mmol) was added and the mixture was allowed to warm to rt and stirred 16 h. The mixture was diluted with water and the aqueous phase was extracted 3× with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4), filtered, concentrated onto silica gel, and purified via column chromatography on silica gel to yield the desired product. C22H25ClFN5O4. 478.2 [M+1]+.
    Figure imgb0404
  • tert-butyl 2-(7-((3-chloro-4-fluorophenyl)carbamoyl)-1H-imidazo[4,5-b]pyridin-2-yl)pyrrolidine-1-carboxylate. A solution of (S)-tert-butyl 2-((2-amino-4-((3-chloro-4-fluorophenyl)carbamoyl)pyridin-3-yl)carbamoyl)pyrrolidine-1-carboxylate (0.094 g, 0.197 mmol) in AcOH (4 mL) was heated to 65 °C for 4 h and to 80 °C for 2 h. The mixture was cooled to rt and concentrated. The residue was partitioned between sat. bicarb solution and EtOAc and the aqueous layer was extracted 3× with EtOAc. The combined organic layers were concentrated onto silica gel and purified via column chromatography on silica gel to yield the desired product. C22H23ClFN5O3. 460.1 [M+1]+.
    Figure imgb0405
  • tert-butyl 2-(7-((3-chloro-4-fluorophenyl)carbamothioyl)-1H-imidazo[4,5-b]pyridin-2-yl)pyrrolidine-1-carboxylate. A mixture of tert-butyl 2-(7-((3-chloro-4-fluorophenyl)carbamoyl)-1H-imidazo[4,5-b]pyridin-2-yl)pyrrolidine-1-carboxylate (0.043 g, 0.093 mmol) and Lawesson's reagent (0.076 g, 0.187 mmol) in toluene (2 mL) was stirred at 95 °C for 16 h. The mixture was cooled to rt, concentrated onto silica gel, and purified via column chromatography on silica gel to yield the desired product. C22H23ClFN5O2S. 476.1 [M+1]+.
    Figure imgb0406
  • tert-butyl 2-(7-(N-(3-chloro-4-fluorophenyl)-N'-hydroxycarbamimidoyl)-1H-imidazo[4,5-b]pyridin-2-yl)pyrrolidine-1-carboxylate. To a mixture of tert-butyl 2-(7-((3-chloro-4-fluorophenyl)carbamothioyl)-1H-imidazo[4,5-b]pyridin-2-yl)pyrrolidine-1-carboxylate (0.019 g, 0.040 mmol) in MeOH (2 mL) was added hydroxylamine (0.12 mL of a 50 w/w% solution in water, 2.00 mmol). The mixture was stirred at 70 °C for 45 min. The mixture was cooled to rt and diluted with brine and EtOAc. The aqueous layer was extracted 4× with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated to yield the desired product. C22H24ClFN6O3. 475.2 [M+1]+.
    Figure imgb0407
  • N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(pyrrolidin-2-yl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide. To a solution of tert-butyl 2-(7-(N-(3-chloro-4-fluorophenyl)-N'-hydroxycarbamimidoyl)-1H-imidazo[4,5-b]pyridin-2-yl)pyrrolidine-1-carboxylate (0.018 g, 0.038 mmol) in DCM (1 mL) was added TFA (1 mL). The mixture stirred at rt for 10 min and was then concentrated. The residue was dissolved in DMSO/water and purified via preparative HPLC to yield the desired product. C17H16ClFN6O. 375.1 [M+1]+.
    • Example 153: 2-Amino-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0408
  • N-(3-chloro-4-fluorophenyl)-2-cyanamido-3-nitroisonicotinamide. A mixture of 2-chloro-N-(3-chloro-4-fluorophenyl)-3-nitroisonicotinamide (1.02 g, 3.09 mmol), cyanamide (260 mg, 6.18 mmol), and potassium carbonate (1.28 g, 9.27 mmol) in dimethylformamide (10 mL) was stirred at 80 °C for 2 hr. The reaction mixture was absorbed onto silica gel and purified by silica gel chromatography to give the desired product (1.03 g). C13H7ClFN5O3. 336.0 (M+1).
    Figure imgb0409
  • 2-amino-N-(3 -chloro-4-fluorophenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide. A mixture of N-(3-chloro-4-fluorophenyl)-2-cyanamido-3-nitroisonicotinamide (1.07 g, 3.20 mmol) and sodium hydrosulfite (1.96 g, 9.59 mmol) in ethanol (10 mL) and dimethyl sulfoxide (10 mL) was stirred at 70 °C for 24 hr. Water was added and the aqueous layer was washed three times with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and absorbed onto silica gel and purified by silica gel chromatography to give the desired product. C13H9ClFN5O. 306.1 (M+1).
    Figure imgb0410
  • 2-Amino-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide. Example 153 was made analogously to Example 107 using 2-amino-N-(3-chloro-4-fluorophenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide in place of N-(3-Chloro-4-fluorophenyl)-2-methyl-1H-imidazo[4,5-b]pyridine-7-carboxamide. C13H10ClFN6O. 321.0 (M+1). 1H NMR (400 MHz, DMSO-d6 ) δ 8.84 (s, 1H), 8.15 - 8.10 (m, 1H), 7.94-7.89 (m, 1H), 7.10 (t, J = 9.0 Hz, 1H), 7.00 - 6.92 (m, 1H), 6.91 - 6.79 (m, 1H), 6.63 - 6.54 (m, 1H).
    • Example 154: N-(3-Chloro-4-fluorophenyl)-2-(cyclopropylamino)-N'-hydroxy-1H-imidazo [4,5-b] pyridine-7-carboximidamide
  • Figure imgb0411
  • N-(3-chloro-4-fluorophenyl)-2-(cyclopropylamino)-1H-imidazo[4,5-b]pyridine-7-carboxamide. Dissolved 2,3-diamino-N-(3-chloro-4-fluorophenyl)isonicotinamide (0.54g, 0.002 mol) in THF (5 ml), to the solution was added cyclopropyl isothiocyanate (0.23g, 0.002 mmol) and triethylamine (1.95g, 0.02 mol). The reaction mixture was heated at 80°C overnight, then to the reaction mixture was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.44 g, 0.002 mol), heated at 80°C for 1h. The reaction mixture was diluted with EtOAc, and then water was added. Product crashed out to afford 200mg desired product. C16H13ClFN5O. 346.1 (M+1).
    Figure imgb0412
  • N-(3-chloro-4-fluorophenyl)-2-(cyclopropylamino)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide. Example 154 was made analogously to Example 107 using the general procedure for hydroxyamidine formation. C16H14ClFN6O. 361.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 11.36 (s, 1H), 8.93 (s, 1H), 8.80 (s, 1H), 8.01 (d, J = 6.1 Hz, 1H), 7.13 - 7.00 (m, 2H), 6.97 (d, J = 6.1 Hz, 1H), 6.55 (ddd, J = 9.0, 4.0, 2.7 Hz, 1H), 2.81 (dq, J = 6.9, 3.4 Hz, 1H), 0.83 (td, J = 7.1, 5.0 Hz, 2H), 0.59 (p, J = 4.7 Hz, 2H).
    • Example 155: N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-(phenylamino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0413
  • Example 155 was made analogously to Example 154 using phenyl isothiocyanate. C19H14ClFN6O 397.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 11.37 (s, 1H), 10.09 (s, 1H), 8.92 (s, 1H), 8.05 (d, J = 6.1 Hz, 1H), 7.66 (d, J = 8.1 Hz, 2H), 7.39 (t, J = 7.7 Hz, 2H), 7.14 - 7.04 (m, 2H), 7.02 (dt, J = 5.6, 2.6 Hz, 2H), 6.60 (ddd, J = 9.0, 4.0, 2.8 Hz, 1H).
    • Example 156: N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-(phenethylamino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0414
  • Example 156 was made analogously to Example 154 using (2-isothiocyanatoethyl)benzene. C21H18ClFN6O. 425.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 11.36 (s, 1H), 8.92 (s, 1H), 7.95 (d, J = 6.3 Hz, 1H), 7.37 - 7.16 (m, 6H), 7.13 - 7.05 (m, 1H), 7.02 (dd, J = 6.5, 2.8 Hz, 1H), 6.96 - 6.85 (m, 1H), 6.57 (ddd, J = 8.9, 4.0, 2.8 Hz, 1H), 3.73 - 3.62 (m, 2H), 2.89 (t, J = 7.3 Hz, 2H).
    • Example 157: N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-((2,2,2-trifluoroethyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0415
  • Example 157 was made analogously to Example 154 using 1,1,1-trifluoro-2-isothiocyanatoethane. C15H11ClF4N6O. 403.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 11.42 (s, 1H), 8.95 (s, 1H), 8.00 (d, J = 6.2 Hz, 1H), 7.05 (ddd, J = 19.0, 8.5, 4.0 Hz, 3H), 6.95 (d, J = 6.5 Hz, 1H), 6.57 (dt, J = 9.0, 3.3 Hz, 1H), 4.30 (s, 3H).
    • Example 158: N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-(methylamino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0416
  • Example 158 was made analogously to Example 154 using methyl isothiocyanate. C14H12ClFN6O. 335.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 12.08 (s, 1H), 11.37 (s, 1H), 8.96 (s, 1H), 7.96 (d, J = 6.2 Hz, 1H), 7.08 (t, J = 9.1 Hz, 1H), 7.03 - 6.97 (m, 1H), 6.91 (d, J = 6.2 Hz, 1H), 6.56 (ddd, J = 9.0, 4.0, 2.8 Hz, 1H), 3.00 (d, J = 4.8 Hz, 3H).
    • Example 159: Isopropyl (7-(N-(3-chloro-4-fluorophenyl)-N'-hydroxycarbamimidoyl)-1H-imidazo[4,5-b]pyridin-2-yl)carbamate
  • Figure imgb0417
  • Isopropyl (7-((3-chloro-4-fluorophenyl)carbamoyl)-1H-imidazo[4,5-b]pyridin-2-yl)carbamate. To a mixture of 2-amino-N-(3-chloro-4-fluorophenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide (30 mg, 0.098mmol) and triethylamine (0.041 mL, 0.29 mmol) in dichloromethane at 0 °C was added solution of isopropyl chloroformate (1 M in toluene, 0.118 mL, 0.118 mmol). The reaction was allowed to warm to room temperature and stirred for 1 hr. Saturated sodium bicarbonate was added and the aqueous layer was washed three times with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was loaded onto a silica gel column and purified by silica gel chromatography to give the desired product mixed with isopropyl 7-((3-chloro-4-fluorophenyl)carbamoyl)-2-((isopropoxycarbonyl)amino)-1H-imidazo[4,5-b]pyridine-1-carboxylate. C17H15ClFN5O3. 392.2 (M+1).
    Figure imgb0418
  • Isopropyl (7-(N-(3-chloro-4-fluorophenyl)-N'-hydroxycarbamimidoyl)-1H-imidazo[4,5-b]pyridin-2-yl)carbamate. Example 159 was made analogously to Example 107 using isopropyl (7-((3-chloro-4-fluorophenyl)carbamoyl)-1H-imidazo[4,5-b]pyridin-2-yl)carbamate in place of N-(3-Chloro-4-fluorophenyl)-2-methyl-1H-imidazo[4,5-b]pyridine-7-carboxamide. C17H16ClFN6O3. 407.0 (M+1). 1H NMR (400 MHz, DMSO-d6 ) δ 8.83 (s, 1H), 8.18 (d, J = 5.4 Hz, 1H), 7.13 (t, J= 9.1 Hz, 1H), 7.02 - 6.91 (m, 2H), 6.67 - 6.57 (m, 1H), 5.00 (dq, J = 6.3, 6.3 Hz, 1H), 1.31 (d, J= 6.2 Hz, 6H).
    • Example 160: Ethyl (7-(N-(3-chloro-4-fluorophenyl)-N'-hydroxycarbamimidoyl)-1H-imidazo[4,5-b]pyridin-2-yl)carbamate
  • Figure imgb0419
  • Example 160 was made analogously to Example 154 using O-ethyl carbonisothiocyanatidate. C16H14ClFN6O3. 393.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 11.54 (s, 1H), 8.83 (s, 1H), 8.20 (d, J = 5.6 Hz, 1H), 7.11 (t, J = 9.1 Hz, 1H), 7.03 (d, J = 5.6 Hz, 1H), 6.95 (dd, J = 6.5, 2.7 Hz, 1H), 6.62 (ddd, J = 8.9, 4.0, 2.7 Hz, 1H), 4.26 (q, J = 7.1 Hz, 2H), 1.28 (t, J = 7.1 Hz, 3H).
    • Example 161: N-(3-Chloro-4-fluorophenyl)-2-((cyclopropylmethyl)amino)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0420
  • Example 161 was made analogously to Example 154 using cyclopropyl methyl isothiocyanate. C17H16ClFN6O. 375.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 11.37 (s, 1H), 8.93 (s, 1H), 7.94 (t, J = 5.3 Hz, 1H), 7.50-7.25 (m, 1H), 7.14-6.97 (m, 2H), 6.91 (d, J = 6.3 Hz, 1H), 6.58 (ddd, J = 9.0, 4.0, 2.7 Hz, 1H), 3.31 (t, J = 6.5 Hz, 2H), 1.11 (d, J = 13.1 Hz, 1H), 0.57 - 0.40 (m, 2H), 0.33 - 0.19 (m, 2H).
    • Example 162: N-(3-Chloro-4-fluorophenyl)-2-((3,3-difluorocyclobutyl)amino)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0421
  • Example 162 was made analogously to Example 154 using 1,1-difluoro-3-isothiocyanatocyclobutane. C17H14ClF3N6O. 411.0 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 11.41 (d, J = 18.8 Hz, 1H), 8.97 (s, 1H), 8.69 (s, 1H), 7.99 (dd, J = 7.9, 6.6 Hz, 1H), 7.09 - 6.97 (m, 2H), 6.94 (d, J = 6.2 Hz, 1H), 6.54 (ddd, J = 9.0, 4.0, 2.8 Hz, 1H), 4.28 (s, 1H), 3.03 (tt, J = 14.3, 7.9 Hz, 2H), 2.77 (d, J = 10.6 Hz, 2H).
    • Example 163: N-(3-Chloro-4-fluorophenyl)-2-(ethylamino)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0422
  • N-(3-chloro-4-fluorophenyl)-2-(ethylamino)-1H-imidazo[4,5-b]pyridine-7-carboxamide was made analogously to Example 154 using ethyl isothiocyanate. C15H13ClFN5O. 333.9 (M+1).
    Figure imgb0423
  • N-(3-chloro-4-fluorophenyl)-2-(ethylamino)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide. Example 163 was made analogously to Example 107 using N-(3-chloro-4-fluorophenyl)-2-(ethylamino)-1H-imidazo[4,5-b]pyridine-7-carboxamide in place of N-(3-Chloro-4-fluorophenyl)-2-methyl-1H-imidazo[4,5-b]pyridine-7-carboxamide. C15H14ClFN6O. 349.1 (M+1).
    • Example 164: N-(3-Chloro-4-fluorophenyl)-2-(cyclobutylamino)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0424
  • N-(3-chloro-4-fluorophenyl)-2-(cyclobutylamino)-1H-imidazo[4,5-b]pyridine-7-carboxamide. Example 164 was made analogously to Example 154 using cyclobutyl isothiocyanate. C17H15ClFN5O. 360.2 (M+1).
    Figure imgb0425
  • N-(3-chloro-4-fluorophenyl)-2-(cyclobutylamino)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide. Example 164 was made analogously to Example 107 using N-(3-chloro-4-fluorophenyl)-2-(cyclobutylamino)-1H-imidazo[4,5-b]pyridine-7-carboxamide in place of N-(3-Chloro-4-fluorophenyl)-2-methyl-1H-imidazo[4,5-b]pyridine-7-carboxamide. C17H16ClFN6O. 375.1 (M+1). 1H NMR (400 MHz, DMSO-d6 ) δ 11.40 (s, 1H), 8.98 (s, 1H), 7.96 (d, J = 6.2 Hz, 1H), 7.09 (t, J = 9.1 Hz, 1H), 7.05 (dd, J = 6.1, 2.5 Hz, 1H), 6.92 (d, J = 6.2 Hz, 1H), 6.62 - 6.50 (m, 1H), 4.34 (q, J = 7.2 Hz, 1H), 2.39 - 2.24 (m, 2H), 2.15 - 1.98 (m, 2H), 1.82 - 1.58 (m, 2H).
    • Example 165: N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-(isopropylamino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0426
  • N-(3-chloro-4-fluorophenyl)-2-(isopropylamino)-1H-imidazo[4,5-b]pyridine-7-carboxamide was made analogously to Example 154 using isopropyl isothiocyanate. C16H15ClFN5O. 348.2 (M+1).
    Figure imgb0427
  • N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(isopropylamino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide. Example 165 was made analogously to Example 107 using N-(3-chloro-4-fluorophenyl)-2-(isopropylamino)-1H-imidazo[4,5-b]pyridine-7-carboxamide in place of N-(3-Chloro-4-fluorophenyl)-2-methyl-1H-imidazo[4,5-b]pyridine-7-carboxamide. C16H16ClFN6O. 363.1 (M+1). 1H NMR (400 MHz, DMSO-d6 ) δ 11.42 (s, 1H), 8.97 (s, 1H), 7.96 (d, J = 6.3 Hz, 1H), 7.11 (t, J = 9.0 Hz, 1H), 7.05 (dd, J = 6.6, 2.7 Hz, 1H), 6.92 (d, J = 6.3 Hz, 1H), 6.62 - 6.56 (m, 1H), 4.06 (sex, J= 6.5 Hz, 1H), 1.25 (d, J = 6.3 Hz, 6H).
    • Example 166: N-(3-Chlorophenyl)-N'-hydroxy-2-(methylamino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0428
  • Example 166 was made analogously to Example 158 using N-(3-chloro-4-fluorophenyl)-2-(methylamino)-1H-imidazo[4,5-b]pyridine-7-carboxamide. C14H13ClN6O, 316.3/318.6 (M+1). 1H NMR (400 MHz, DMSO-d6 ) δ 11.42 (br. s, 1H), 8.97 (s, 1H), 7.97 (d, J = 6.3 Hz, 1H), 7.06 (t, J = 8.1 Hz, 1H), 6.99 - 6.79 (m, 2H), 6.62 - 6.43 (m, 1H), 3.01 (d, J = 4.8 Hz, 3H).
    • Example 167: N-(3-Chloro-4-fluorophenyl)-2-((2-(diethylamino)ethyl)amino)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0429
  • 1H-Imidazo[4,5-b]pyridine-7-carboxylic acid (10 g, 61 mmol, 1 equiv) was dissolved in methanol (160 mL), H2SO4 (10 mL, 189 mmol, 3.08 equiv) was added, and the reaction was stirred at 80 °C for overnight. The reaction was carefully quenched by the addition of a solution of NaOMe in methanol (80 mL, 13 wt% solution, 189 mmol, 3.08 equiv) at 0 °C. Methanol was subsequently removed in vacuo, the resulting solid was slurried in water and filtered. The solid was dried in a vacuum oven (65 °C) overnight. Methyl 1H-imidazo[4,5-b]pyridine-7-carboxylate was obtained as a brown solid. C8H7N3O2, 178.06 (M+1).
  • To a suspension of methyl 1H-imidazo[4,5-b]pyridine-7-carboxylate (7.8 g, 44 mmol, 1 equiv) in a mixture of THF/DMF (70 mL, 6:1 ratio) was added a 60 wt% dispersion of NaH (2.1 g, 53 mmol, 1.2 equiv) in three portions. Once gas evolution ceased, the reaction mixture was cooled to 0 °C and SEM-Cl (9.3 mL, 53 mmol, 1.2 equiv) was added. The ice bath was subsequently removed and the reaction was stirred at room temperature for 3 hours before being quenched with saturated aqueous NH4Cl. The reaction mixture was diluted with water and extracted three times with EtOAc. The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (0-5% MeOH/CH2Cl2 over 20 minutes). Methyl 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridine-7-carboxylate was isolated as a yellow solid. C14H21N3O3Si. 308.01 (M+1).
    Figure imgb0430
  • To a solution of methyl 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridine-7-carboxylate (1.1 g, 4 mmol, 1 equiv) in acetonitrile (23.1 mL) was added NCS (0.72 g, 5 mmol, 1.5 equiv). The reaction mixture was stirred at 100 °C in a sealed vessel for 12 hours. Acetonitrile was subsequently removed in vacuo and the crude product purified by silica gel chromatography (0-5% MeOH/CH2Cl2 over 20 minutes). methyl 2-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridine-7-carboxylate was obtained as a yellow solid. C14H20ClN3O3Si. 341.94/343.93 (M+1).
    Figure imgb0431
  • The above compound was made analogously to Example 39 using N,N-diethylethane-1,2-diamine in place of N,N-dimethylpropane-1,3-diamine and methyl 2-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridine-7-carboxylate in place of methyl 2-chloro-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-7-carboxylate. The TFA salt of methyl 2-((2-(diethylamino)ethyl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridine-7-carboxylate was obtained as a yellow oil. C20H35N5O3Si. 422.23 (M+1).
    Figure imgb0432
  • The above compound was made analogously to Example 39 using methyl 2-((2-(diethylamino)ethyl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridine-7-carboxylate in place of methyl 2-((3-(dimethylamino)propyl)amino)-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-7-carboxylate. The TFA salt of N-(3-chloro-4-fluorophenyl)-2-((2-(diethylamino)ethyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboxamide was isolated as a white solid. C19H22ClFN6O. 405.21/407.14 (M+1).
    Figure imgb0433
  • N-(3-chloro-4-fluorophenyl)-2-((2-(diethylamino)ethyl)amino)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide was made analogously to Example 59 using N-(3-chloro-4-fluorophenyl)-2-((2-(diethylamino)ethyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboxamide in place of N-(3-chloro-4-fluorophenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide. The TFA salt of N-(3-chloro-4-fluorophenyl)-2-((2-(diethylamino)ethyl)amino)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide was isolated as a white solid. C19H23ClFN7O. 420.16/422.13 (M+1). 1H NMR (400 MHz, DMSO-d6 ) δ 11.30 (s, 1H), 8.93 (s, 1H), 7.97 (d, J = 6.2 Hz, 1H), 7.09 (t, J = 9.0 Hz, 1H), 6.99 (dd, J = 6.5, 2.7 Hz, 1H), 6.94 (d, J = 6.0 Hz, 1H), 6.56 (ddd, J = 9.0, 4.0, 2.7 Hz, 1H), 3.75 (m, 2H), 3.32 (t, J = 6.1 Hz, 2H), 3.23 (q, J = 7.2 Hz, 4H), 1.21 (t, J = 7.2 Hz, 6H). 19F NMR (376 MHz, DMSO-d6 ) δ -74.40 (9F), -126.69 (1F).
    • Example 168: N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-((2-morpholinoethyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0434
  • The above compound was made analogously to Example 39 using 2-morpholinoethanamine in place of N,N-dimethylpropane-1,3-diamine and methyl 2-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridine-7-carboxylate in place of methyl 2-chloro-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-7-carboxylate. The TFA salt of methyl 2-((2-morpholinoethyl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridine-7-carboxylate was isolated as a yellow oil. C20H33N5O4Si. 436.21 (M+1).
    Figure imgb0435
  • The above compound was made analogously to Example 39 using methyl 2-((2-morpholinoethyl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridine-7-carboxylate in place of methyl 2-((3-(dimethylamino)propyl)amino)-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-7-carboxylate. The TFA salt of N-(3-chloro-4-fluorophenyl)-2-((2-morpholinoethyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboxamide was isolated as a white solid. C19H20ClFN6O2. 419.22/421.14 (M+1).
    Figure imgb0436
  • N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-((2-morpholinoethyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide was made analogously to Example 59 using N-(3-chloro-4-fluorophenyl)-2-((2-morpholinoethyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboxamide in place of N-(3-chloro-4-fluorophenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide. The TFA salt of N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((2-morpholinoethyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide was isolated as a white solid. C19H21ClFN7O2. 434.16/436.14 (M+1). 1H NMR (400 MHz, DMSO-d6 ) δ 11.31 (br s, 1H), 10.11 (br s, 1H), 8.94 (s, 1H), 7.98 (d, J = 6.2 Hz, 1H), 7.10 (t, J = 9.1 Hz, 1H), 7.00 (dd, J = 6.6, 2.7 Hz, 1H), 6.94 (d, J = 6.1 Hz, 1H), 6.57 (ddd, J = 9.0, 4.0, 2.8 Hz, 1H), 3.87 - 3.71 (m, 8H), 3.44 - 3.20 (m, 4H). 19F NMR (376 MHz, DMSO-d6 ) δ -74.51 (9F), -126.65 (1F).
    • Example 169: N-(3-Chloro-4-fluorophenyl)-2-(dimethylamino)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0437
  • Methyl 2-(dimethylamino)-1H-imidazo[4,5-b]pyridine-7-carboxylate. Dissolved methyl 2,3-diaminoisonicotinate (0.2g, 1 mmol) in DCM (5 mL), to the solution was added phosgeniminium chloride (0.39g, 2 mmol) and triethylamine (0.6g, 6 mmol). The reaction mixture was stirred at 40 degree for 3h. Then the reaction was quenched with NaHCO3 solution, diluted with EtOAc, evaporated organic solvent, the residue was purified with Combi-Flash column to afford the desired product. C10H12N4O2. 221.1 (M+1).
    Figure imgb0438
  • N-(3-chloro-4-fluorophenyl)-2-(dimethylamino)-1H-benzo[d]imidazole-7-carboxamide was made analogously to Example 23 using Methyl 2-(dimethylamino)-1H-imidazo[4,5-b]pyridine-7-carboxylate. C16H14ClFN4O. 334.2 (M+1).
    Figure imgb0439
  • N-(3-chloro-4-fluorophenyl)-2-(dimethylamino)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide. Example 169 was made analogously to Example 107 using the general procedure for hydroxyamidine formation. C15H14ClFN6O. 349.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 11.36 (d, J = 9.1 Hz, 1H), 10.09 (s, 1H), 9.00 (s, 1H), 7.94 (d, J = 6.3 Hz, 1H), 7.12 - 6.98 (m, 2H), 6.90 (d, J = 6.3 Hz, 1H), 6.54 (ddd, J = 9.0, 4.0, 2.7 Hz, 1H), 3.87 (s, 6H).
    • Example 170: 2-(Chloromethyl)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-N'-hydroxy-3H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0440
  • 2,3-diamino-N-(4-fluoro-3-(trifluoromethyl)phenyl)isonicotinamide. To a solution of 3-fluoro-4-trifluromethyl-aniline (0.1 g, 0.65 mmol), 2,3-diaminoisonicotinic acid (0.234 g, 1 mmol) and triethylamine (0.18 mL, 1 mmol) in DMF (2 mL) was added HATU (0.186 g, 0.78 mmol). The reaction stirred for 16 hr at RT. Saturated sodium bicarbonate was added and the aqueous layer was washed three times with AcOEt. The combined organic layers were dried over sodium sulfate, filtered and concentrated onto silica gel and purified by silica gel chromatography (0->100% ethyl acetate in hexanes) to give the desired product as yellow crystals. C13H10F4N4O. 315.1 (M+1).
    Figure imgb0441
  • N-(4-fluoro-3-(trifluoromethyl)phenyl)-2-(hydroxymethyl)-3H-imidazo[4,5-b]pyridine-7-carboxamide. 2,3-diamino-N-(4-fluoro-3-(trifluoromethyl)phenyl)isonicotinamide (0.078 g, 0.25 mmol) and 2-hydroxyacetic acid (0.378 g, 5 mmol) was heated neat in a microwave reactor to 170 C for 20 min. LiOH (0.15 g, 6 mmol) in dioxane/ water (0.6/ 2 mL) was added and stirred for 30 min. Saturated sodium bicarbonate was added and the aqueous layer was washed three times with AcOEt. The combined organic layers were dried over sodium sulfate, filtered to give the desired product. C15H10F4N4O2. 355.1 (M+1).
    Figure imgb0442
  • 2-(Chloromethyl)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-N'-hydroxy-3H-imidazo[4,5-b]pyridine-7-carboximidamide. N-(4-fluoro-3-(trifluoromethyl)phenyl)-2-(hydroxymethyl)-3H-imidazo[4,5-b]pyridine-7-carboxamide (0.22 g, 0.62 mmol), POCl3 (0.6 ml, 6 mM) and PCL5 (0.26g, 0.1 mM) was stirred in dioxane (0.6 ml) at RT for 30 min. Volatiles were removed and excess NH2OH in acetonitrile (2 ml, 1/10 50% NH2OH in water/ acetonitrile) was added, stirred at RT for 10 min. Volatiles were removed. Purification by preparatory HPLC (5-100% MeCN in water, 0.1% TFA) afforded the desired product. C15H10ClF4N5O. 386.1.08 (M-1).
    • Example 171: N-(4-Fluoro-3-(trifluoromethyl)phenyl)-N'-hydroxy-2-(hydroxymethyl)-3H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0443
  • 2-(Chloromethyl)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-N'-hydroxy-3H-imidazo[4,5-b]pyridine-7-carboximidamide. (0.006 g, 0.17 mM), NaI (0.010g, 0.67 mM) and NaOAc (0.010g, 1.7 mM) were stirred in acetone (3 ml) at RT for 30 min. After filtration, volatiles were removed. Purification by preparatory HPLC (5-100% MeCN in water, 0.1% TFA) afforded the desired product. C15H11F4N5O2. Exact Mass: 370.1 (M+1).
    • Example 172: N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-(1-hydroxyethyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0444
  • A suspension of 2,3-diamino-N-(3-chloro-4-fluorophenyl)isonicotinamide (200 mg, 0.713 mmol) and 2-hydroxypropanoic acid (1.0 mL, 13 mmol) was sparged with argon for 1 min, then sealed and stirred at 180 °C for 1 h in a microwave reactor. The resulting mixture was cooled to room temperature and treated with 1 M lithium hydroxide (20 mL, 20 mmol), then stirred for 30 min. The resulting precipitate was filtered off and rinsed with water to afford N-(3-chloro-4-fluorophenyl)-2-(1-hydroxyethyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide. C15H12ClFN4O2. 335.1 (M+1).
    Figure imgb0445
  • N-(3-chloro-4-fluorophenyl)-2-(1-((triisopropylsilyl)oxy)ethyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide was made analogously to Example 183 using N-(3-chloro-4-fluorophenyl)-2-(1-hydroxyethyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide in place of N-(3-chloro-4-fluorophenyl)-2-(2-hydroxyethyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide. C24H32ClFN4O2Si. 491.2 (M+1).
    Figure imgb0446
  • N-(3-chloro-4-fluorophenyl)-2-(1-((triisopropylsilyl)oxy)ethyl)-1H-imidazo[4,5-b]pyridine-7-carbothioamide was made analogously to Example 183 using N-(3-chloro-4-fluorophenyl)-2-(1-((triisopropylsilyl)oxy)ethyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide in place of N-(3-chloro-4-fluorophenyl)-2-(2-((triisopropylsilyl)oxy)ethyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide. C24H32ClFN4OSSi. 507.2 (M+1).
    Figure imgb0447
  • A suspension of N-(3-chloro-4-fluorophenyl)-2-(1-((triisopropylsilyl)oxy)ethyl)-1H-imidazo[4,5-b]pyridine-7-carbothioamide (30 mg, 0.059 mmol) in methanol (3 mL) was treated with hydrogen chloride (4.0 M solution in dioxane, 0.12 mL, 0.46 mmol). The resulting solution was stirred at 70 °C overnight, then cooled to room temperature, treated with an additional quantity of hydrogen chloride (4.0 M solution in dioxane, 0.12 mL, 0.46 mmol), and stirred at 70 °C for an additional 7 h. The reaction mixture was then cooled to room temperature and concentrated under reduced pressure. The resulting residue was taken up in methanol (2.4 mL), treated with hydroxylamine (50% solution in water, 0.370 mL, 6.0 mmol), and stirred at 70 °C for 2 h in a sealed vial. The mixture was then cooled to room temperature, diluted with dimethyl sulfoxide, and purified by reverse phase preparative HPLC to provide N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(1-hydroxyethyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide. C15H13ClFN5O2. 350.1 (M+1).
    • Example 173: N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-(hydroxy(phenyl)methyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0448
  • A suspension of 2,3-diamino-N-(3-chloro-4-fluorophenyl)isonicotinamide (400 mg, 1.43 mmol) and 2-hydroxy-2-phenylacetic acid acid (1.74 g, 11.4 mmol) in dioxane (3.5 mL) was sparged with argon for 1 min, then sealed and stirred at 180 °C for 1 h in a microwave reactor. The resulting mixture was cooled to room temperature and treated with 1 M lithium hydroxide (14.3 mL, 14.3 mmol), then stirred for 30 min. The resulting precipitate was filtered off and rinsed with water to afford N-(3-chloro-4-fluorophenyl)-2-(hydroxy(phenyl)methyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide. C20H14ClFN4O2. 397.1 (M+1).
    Figure imgb0449
  • 2-(((tert-butyldimethylsilyl)oxy)(phenyl)methyl)-N-(3-chloro-4-fluorophenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide was made analogously to Example 183 using N-(3-chloro-4-fluorophenyl)-2-(hydroxy(phenyl)methyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide and tert-butyldimethylsilyl trifluoromethanesulfonate in place of N-(3-chloro-4-fluorophenyl)-2-(2-hydroxyethyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide and triisopropylsilyl trifluoromethanesulfonate. C26H28ClFN4O2Si. 511.2 (M+1).
    Figure imgb0450
  • 2-(((tert-butyldimethylsilyl)oxy)(phenyl)methyl)-N-(3-chloro-4-fluorophenyl)-1H-imidazo[4,5-b]pyridine-7-carbothioamide was made analogously to Example 183 using 2-(((tert-butyldimethylsilyl)oxy)(phenyl)methyl)-N-(3-chloro-4-fluorophenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide in place of N-(3-chloro-4-fluorophenyl)-2-(2-((triisopropylsilyl)oxy)ethyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide. C26H28ClFN4OSSi. 527.1 (M+1).
    Figure imgb0451
  • Example 173 was made analogously to Example 172 using 2-(((tert-butyldimethylsilyl)oxy)(phenyl)methyl)-N-(3-chloro-4-fluorophenyl)-1H-imidazo[4,5-b]pyridine-7-carbothioamide in place of N-(3-chloro-4-fluorophenyl)-2-(1-((triisopropylsilyl)oxy)ethyl)-1H-imidazo[4,5-b]pyridine-7-carbothioamide. C20H15ClFN5O2. 413.0 (M+1).
    • Example 174: N-(3-Chloro-4-fluorophenyl)-2-(cyclopropyl(hydroxy)methyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0452
  • N-(3-chloro-4-fluorophenyl)-2-(cyclopropyl(hydroxy)methyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide was made analogously to Example 173 using 2-cyclopropyl-2-hydroxyacetic acid in place of 2-hydroxy-2-phenylacetic acid acid. C17H14ClFN4O2. 361.1 (M+1).
    Figure imgb0453
  • 2-(((tert-butyldimethylsilyl)oxy)(cyclopropyl)methyl)-N-(3-chloro-4-fluorophenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide was made analogously to Example 183 using N-(3-chloro-4-fluorophenyl)-2-(cyclopropyl(hydroxy)methyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide and tert-butyldimethylsilyl trifluoromethanesulfonate in place of N-(3-chloro-4-fluorophenyl)-2-(2-hydroxyethyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide and triisopropylsilyl trifluoromethanesulfonate. C23H28ClFN4O2Si. 475.2 (M+1).
    Figure imgb0454
  • 2-(((tert-butyldimethylsilyl)oxy)(cyclopropyl)methyl)-N-(3-chloro-4-fluorophenyl)-1H-imidazo[4,5-b]pyridine-7-carbothioamide was made analogously to Example 183 using 2-(((tert-butyldimethylsilyl)oxy)(cyclopropyl)methyl)-N-(3-chloro-4-fluorophenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide in place of N-(3-chloro-4-fluorophenyl)-2-(2-((triisopropylsilyl)oxy)ethyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide. C23H28ClFN4OSSi. 491.2 (M+1).
    Figure imgb0455
  • Example 175 was made analogously to Example 172 using 2-(((tert-butyldimethylsilyl)oxy)(cyclopropyl)methyl)-N-(3-chloro-4-fluorophenyl)-1H-imidazo[4,5-b]pyridine-7-carbothioamide in place of N-(3-chloro-4-fluorophenyl)-2-(1-((triisopropylsilyl)oxy)ethyl)-1H-imidazo[4,5-b]pyridine-7-carbothioamide. C17H15ClFN5O2. 376.1 (M+1).
    • Example 175: N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-(2-hydroxypropan-2-yl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0456
  • A suspension of 2,3-diamino-N-(3-chloro-4-fluorophenyl)isonicotinamide (400 mg, 1.43 mmol) and 2-hydroxy-2-methylpropanoic acid (1.19 g, 11.4 mmol) in dioxane (2 mL) was sparged with argon for 1 min, then sealed and stirred at 180 °C for 1 h in a microwave reactor. The resulting mixture was cooled to room temperature and treated with 1 M lithium hydroxide (14.3 mL, 14.3 mmol), then stirred for 30 min. The mixture was then filtered, and the resulting filtrate was acidified with 2 M hydrochloric acid to give a precipitate. The solids were filtered off and washed with water to provide N-(3-chloro-4-fluorophenyl)-2-(2-hydroxypropan-2-yl)-1H-imidazo[4,5-b]pyridine-7-carboxamide. C16H14ClFN4O2. 349.1 (M+1).
    Figure imgb0457
  • 2-(2-((tert-butyldimethylsilyl)oxy)propan-2-yl)-N-(3-chloro-4-fluorophenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide was made analogously to Example 183 using N-(3-chloro-4-fluorophenyl)-2-(2-hydroxypropan-2-yl)-1H-imidazo[4,5-b]pyridine-7-carboxamide and tert-butyldimethylsilyl trifluoromethanesulfonate in place of N-(3-chloro-4-fluorophenyl)-2-(2-hydroxyethyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide and triisopropylsilyl trifluoromethanesulfonate. C22H28ClFN4O2Si. 463.2 (M+1).
    Figure imgb0458
  • 2-(2-((tert-butyldimethylsilyl)oxy)propan-2-yl)-N-(3-chloro-4-fluorophenyl)-1H-imidazo[4,5-b]pyridine-7-carbothioamide was made analogously to Example 183 using 2-(2-((tert-butyldimethylsilyl)oxy)propan-2-yl)-N-(3-chloro-4-fluorophenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide in place of N-(3-chloro-4-fluorophenyl)-2-(2-((triisopropylsilyl)oxy)ethyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide. C22H28ClFN4OSSi. 479.1 (M+1).
    Figure imgb0459
  • Example 175 was made analogously to Example 172 using 2-(2-((tert-butyldimethylsilyl)oxy)propan-2-yl)-N-(3-chloro-4-fluorophenyl)-1H-imidazo[4,5-b]pyridine-7-carbothioamide in place of N-(3-chloro-4-fluorophenyl)-2-(1-((triisopropylsilyl)oxy)ethyl)-1H-imidazo[4,5-b]pyridine-7-carbothioamide. C16H15ClFN5O2. 364.1 (M+1).
    • Example 176: -N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-(2,2,2-trifluoro-1-hydroxyethyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0460
  • N-(3-chloro-4-fluorophenyl)-2-(2,2,2-trifluoro-1-hydroxyethyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide was made analogously to Example 175 using 3,3,3-trifluoro-2-hydroxypropanoic acid in place of 2-hydroxy-2-methylpropanoic acid. C15H9ClF4N4O2. 389.0 (M+1).
    Figure imgb0461
  • 2-(1-((tert-Butyldimethylsilyl)oxy)-2,2,2-trifluoroethyl)-N-(3-chloro-4-fluorophenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide was made analogously to Example 183 using N-(3-chloro-4-fluorophenyl)-2-(2,2,2-trifluoro-1-hydroxyethyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide and tert-butyldimethylsilyl trifluoromethanesulfonate in place of N-(3-chloro-4-fluorophenyl)-2-(2-hydroxyethyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide and triisopropylsilyl trifluoromethanesulfonate. C21H23ClF4N4O2Si. 503.1 (M+1).
    Figure imgb0462
  • 2-(1-((tert-butyldimethylsilyl)oxy)-2,2,2-trifluoroethyl)-N-(3-chloro-4-fluorophenyl)-1H-imidazo[4,5-b]pyridine-7-carbothioamide was made analogously to Example 183 using 2-(1-((tert-butyldimethylsilyl)oxy)-2,2,2-trifluoroethyl)-N-(3-chloro-4-fluorophenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide in place of N-(3-chloro-4-fluorophenyl)-2-(2-((triisopropylsilyl)oxy)ethyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide. C21H23ClF4N4OSSi. 519.1 (M+1).
    Figure imgb0463
  • Example 176 was made analogously to Example 172 using 2-(1-((tert-butyldimethylsilyl)oxy)-2,2,2-trifluoroethyl)-N-(3-chloro-4-fluorophenyl)-1H-imidazo[4,5-b]pyridine-7-carbothioamide in place of N-(3-chloro-4-fluorophenyl)-2-(1-((triisopropylsilyl)oxy)ethyl)-1H-imidazo[4,5-b]pyridine-7-carbothioamide. C15H10ClF4N5O2. 404.1 (M+1).
    • Example 177: N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-(hydroxymethyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0464
  • A solution of 4-(3-chloro-4-fluorophenyl)-3-(2-(hydroxymethyl)-1H-imidazo[4,5-b]pyridin-7-yl)-1,2,4-oxadiazol-5(4H)-one (20 mg, 0.055 mmol) in tetrahydrofuran (0.75 mL) was treated with water (0.75 mL) followed by 2 M sodium hydroxide (0.75 mL, 1.5 mmol). The mixture was stirred for 20 min, then acidified with acetic acid and purified by reverse phase preparative HPLC to provide the desired product. C14H11ClFN5O2. 336.1 (M+1).
    • Example 178: N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-((methylamino)methyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0465
  • Example 178 was made analogously to Example 112 using methylamine (2.0 M solution in THF) in place of morpholine. C15H14ClFN6O. 349.1 (M+1).
    • Example 179: 2-(Aminomethyl)-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0466
  • A solution of (7-(4-(3-chloro-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-1-(methylsulfonyl)-1H-imidazo[4,5-b]pyridin-2-yl)methyl methanesulfonate (10 mg, 0.019 mmol) in acetonitrile (0.5 mL) was treated with ammonia (0.5 M solution in dioxane, 0.50 mL, 0.25 mmol) and stirred at room temperature overnight. The mixture was then concentrated under reduced pressure. The resulting residue was taken up in tetrahydrofuran (0.50 mL) and treated with water (0.50 mL) followed by 2 M sodium hydroxide (0.20 mL, 0.40 mmol). The resulting mixture was stirred at room temperature for 5 min, then acidified with acetic acid and purified by reverse phase preparative HPLC to provide the desired product. C14H12ClFN6O. 335.1 (M+1).
    • Example 180: N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-(phenylsulfonamidomethyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0467
  • A solution of (7-(4-(3-chloro-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-1-(methylsulfonyl)-1H-imidazo[4,5-b]pyridin-2-yl)methyl methanesulfonate (36 mg, 0.069 mmol) in acetonitrile (2 mL) was treated with ammonia (0.5 M solution in dioxane, 1.9 mL, 0.97 mmol) and stirred at room temperature overnight. The mixture was then concentrated under reduced pressure. The resulting residue was dissolved in dichloromethane (2 mL) and treated with pyridine (0.054 mL, 0.67 mmol) and divided into two batches of equal volume. One of these batches was then cooled to 0 °C and benzenesulfonyl chloride (0.78 M solution in dichloromethane, 0.130 mL, 0.100 mmol) was added dropwise with stirring. The reaction mixture was then warmed to room temperature and stirred for 10 min, then cooled to 0 °C and treated with water. The mixture was then partially concentrated under reduced pressure, then treated with tetrahydrofuran (1 mL) followed by 2 M sodium hydroxide (1 mL) and stirred for 15 min. The mixture was then acidified with acetic acid, partially concentrated under reduced pressure, diluted with dimethyl sulfoxide (1 mL), and purified by reverse phase preparative HPLC to provide the desired product. C20H16ClFN6O3S. 475.1 (M+1).
    • Example 181: N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-(methylsulfonamidomethyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0468
  • Example 181 was prepared analogously to Example 180 using methanesulfonyl chloride in place of benzenesulfonyl chloride. C15H14ClFN6O3S. 413.0 (M+1).
    • Example 182: N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-((pyrimidin-2-ylamino)methyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0469
  • A solution of (7-(4-(3-chloro-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-1-(methylsulfonyl)-1H-imidazo[4,5-b]pyridin-2-yl)methyl methanesulfonate (59 mg, 0.114 mmol) in acetonitrile (3 mL) was treated with ammonia (0.5 M solution in dioxane, 1.9 mL, 0.97 mmol) and stirred at room temperature overnight. The solution was then divided into two batches of equal volume. One of the batches was concentrated under reduced pressure and the resulting residue taken up in DMSO (1 mL). The solution was treated with N,N-diisopropylethylamine (0.061 mL, 0.35 mmol) followed by 2-fluoropyrmidine (23 mg, 0.23 mmol) and stirred for at room temperature for 48 h. The mixture was then treated with water (1 mL) and 2 M sodium hydroxide (0.5 mL) and stirred for 15 min, then acidified acetic acid, diluted with dimethyl sulfoxide, and purified by reverse phase preparative HPLC to provide the desired product. C18H14ClFN8O. 413.1 (M+1).
    • Example 183: N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-(2-hydroxyethyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0470
  • Ethyl 2-(7-((3-chloro-4-fluorophenyl)carbamoyl)-1H-imidazo[4,5-b]pyridin-2-yl)acetate. A suspension of 2,3-diamino-N-(3-chloro-4-fluorophenyl)isonicotinamide (10.9 g, 38.8 mmol) and ethyl 3-ethoxy-3-iminopropanoate hydrochloride (30.4 g, 155 mmol) in ethanol (100 mL) was stirred at 80 °C for 24 h. The mixture was then cooled to room temperature and an additional portion of ethyl 3-ethoxy-3-iminopropanoate hydrochloride (30.4 g, 155 mmol) was added. The suspension was stirred at 80 °C for an additional 24 h. The mixture was then cooled to room temperature and the resulting solid filtered off, rinsed with water, and dried under a stream of air to afford the desired product. C17H14ClFN4O3. 377.1 (M+1).
    Figure imgb0471
  • N-(3-chloro-4-fluorophenyl)-2-(2-hydroxyethyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide. To a stirring suspension of ethyl 2-(7-((3-chloro-4-fluorophenyl)carbamoyl)-1H-imidazo[4,5-b]pyridin-2-yl)acetate (5.55 g, 14.7 mmol) in THF (210 mL) under a positive pressure of nitrogen was added lithium borohydride (3.21 g, 147 mmol) in five equal portions. The resulting mixture was then stirred at 40 °C for 1 h. The mixture was then cooled to 0 °C and water (83 mL) was slowly added, such that the internal temperature was kept below 15 °C. After 30 min of stirring, 1M hydrochloric acid (660 mL) was slowly added, such that the internal temperature was kept below 20 °C. The mixture was then heated to 40 °C and stirred for 2 h. The resulting solution was cooled to room temperature and extracted with ethyl acetate (3 x 500 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford the desired product (2.46 g). The aqueous layer contained a yellow precipitate which was filtered off, rinsed with water, and dried under a stream of air to afford an additional quantity of desired product. C15H12ClFN4O2. 335.1 (M+1).
    Figure imgb0472
  • N-(3-chloro-4-fluorophenyl)-2-(2-((triisopropylsilyl)oxy)ethyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide. To a stirring suspension of N-(3-chloro-4-fluorophenyl)-2-(2-hydroxyethyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide (2.46 g, 7.35 mmol) in dichloromethane (75 mL) under a nitrogen atmosphere was added 2,6-lutidine (10.2 mL, 88.2 mmol). The mixture was then cooled to 0 °C and triisopropylsilyl trifluoromethanesulfonate (11.9 mL, 44.1 mmol) was added dropwise with stirring. The mixture was then allowed to warm to room temperature and stirred for an additional 90 min. Water was added with vigorous stirring, then the organic and aqueous layers were separated and the organic layer washed four additional times with water. The organic layer was then adsorbed onto silica gel and purified by flash chromatography (0-100% EtOAc/hexanes). Product-containing fractions were combined and concentrated under reduced pressure, then triturated with acetonitrile to afford the desired product. C24H32ClFN4O2Si. 491.4 (M+1).
    Figure imgb0473
  • N-(3-chloro-4-fluorophenyl)-2-(2-((triisopropylsilyl)oxy)ethyl)-1H-imidazo[4,5-b]pyridine-7-carbothioamide. A suspension of N-(3-chloro-4-fluorophenyl)-2-(2-((triisopropylsilyl)oxy)ethyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide (2.27 g, 4.62 mmol) and 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane 2,4-disulfide (3.74 g, 9.24 mmol) in toluene (92 mL) was stirred at 95 °C for 4 h. The mixture was then cooled to room temperature and filtered, rinsing with dichloromethane. The combined filtrates were adsorbed onto silica gel and purified by flash chromatography (0-75% EtOAc/hexanes) to provide the desired product. C24H32ClFN4OSSi. 507.2 (M+1).
    Figure imgb0474
  • N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(2-hydroxyethyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide. A solution of 4-(3-chloro-4-fluorophenyl)-3-(2-(2-((triisopropylsilyl)oxy)ethyl)-1H-imidazo[4,5-b]pyridin-7-yl)-1,2,4-oxadiazol-5(4H)-one (40mg, 0.079mmol) and hydrogen chloride (4.0 M solution in dioxane, 0.158 mL, 0.631 mmol) in methanol (4 mL) was stirred at 70 °C overnight in a sealed screw-top flask. The mixture was then cooled to room temperature and concentrated under reduced pressure. The resulting residue was taken up in hydroxylamine (50% solution in water, 0.259 mL, 3.991mmol) in methanol (1.6 mL) was stirred at 70 °C in a sealed screw-top flask for 1 h. The mixture was then cooled to room temperature The mixture was acidified with acetic acid (0.300 mL, 5.24 mmol), diluted with dimethyl sulfoxide (4 mL), and purified by reverse phase preparative HPLC to provide the desired product. C15H13ClFN5O2. 350.10 (M+1).
    • Example 184: N-(3-Chloro-4-fluorophenyl)-2-(2-(dimethylamino)ethyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0475
  • 4-(3-chloro-4-fluorophenyl)-3-(2-(2-((triisopropylsilyl)oxy)ethyl)-1H-imidazo[4,5-b]pyridin-7-yl)-1,2,4-oxadiazol-5(4H)-one. A suspension of N-(3-chloro-4-fluorophenyl)-2-(2-((triisopropylsilyl)oxy)ethyl)-1H-imidazo[4,5-b]pyridine-7-carbothioamide (1.70 g, 3.33 mmol) and hydroxylamine (50% solution in water, 20.4 mL, 333 mmol) in methanol (135 mL) was stirred at 70 °C in a sealed screw-top flask for 1 h. The mixture was then cooled to room temperature and partially concentrated under reduced pressure to afford a white aqueous suspension. The solids were filtered off and dried under reduced pressure, then taken up in ethyl acetate (135 mL) and treated with 1,1'-carbonyldiimidazole (702 mg, 4.33 mmol). The mixture was stirred at 30 °C for 1 h, then adsorbed onto silica gel and purified by flash chromatography (0-100% EtOAc/hexanes) to provide the desired product. C25H31ClFN5O3Si. 532.2 (M+1).
    Figure imgb0476
  • 2-(7-(4-(3-chloro-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-1-(methylsulfonyl)-1H-imidazo[4,5-b]pyridin-2-yl)ethyl methanesulfonate. A solution of 4-(3-chloro-4-fluorophenyl)-3-(2-(2-((triisopropylsilyl)oxy)ethyl)-1H-imidazo[4,5-b]pyridin-7-yl)-1,2,4-oxadiazol-5(4H)-one (1.95 g, 3.67 mmol) and hydrogen chloride (4.0 M solution in dioxane, 7.3 mL, 29 mmol) in methanol (180 mL) was stirred at 70 °C overnight in a sealed screw-top flask. The mixture was then cooled to room temperature and concentrated under reduced pressure. The resulting residue was taken up in dichloromethane (75 mL), treated with N,N-diisopropylethylamine (6.4 mL, 37 mmol), and cooled to 0 °C under a nitrogen atmosphere. Methanesulfonyl chloride (2.0 mL, 26 mmol) was added dropwise over 5 min with stirring. After 30 min, the mixture was treated with water, the layers were separated, and the organic layer was washed twice more with water. The organic phase was then concentrated under reduced pressure and purified by flash chromatography (0-65% EtOAc/hexanes) to provide the desired product (Note: the connectivity of the methanesulfonyl group on the imidazole ring was assumed to be at N(1) as indicated, though connectivity at N(3) was not rigorously ruled out). C18H15ClFN5O7S2. 532.1 (M+1).
    Figure imgb0477
  • A solution of 2-(7-(4-(3-chloro-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-1-(methylsulfonyl)-3H-imidazo[4,5-b]pyridin-2-yl)ethyl methanesulfonate (20 mg, 0.038 mmol) in acetonitrile (0.2 mL) was treated with dimethylamine (2.0 M solution in tetrahydrofuran, 0.38 mL, 0.75 mmol), and the resulting solution was stirred at room temperature for 1 h. The mixture was then concentrated under reduced pressure. The resulting residue was taken up in tetrahydrofuran (0.5 mL), treated with water (0.5 mL) followed by 2M sodium hydroxide (0.23 mL, 0.46 mmol), and stirred at room temperature for 15 min. The mixture was acidified with acetic acid (0.064 mL, 1.1 mmol), diluted with dimethyl sulfoxide (3 mL), and purified by reverse phase preparative HPLC to provide the desired product. C17H18ClFN6O. 377.1 (M+1). 1H NMR (400 MHz, DMSO-d6 ) δ 11.11 (s, 1H), 8.91 (s, 1H), 8.31 (d, J = 5.1 Hz, 1H), 7.15 (d, J = 5.1 Hz, 1H), 7.05 (t, J = 9.1 Hz, 1H), 6.93 (dd, J= 6.5, 2.7 Hz, 1H), 6.51 (ddd, J= 9.0, 4.1, 2.7 Hz, 1H), 3.54 (t, J= 7.3 Hz, 2H), 3.30 (t, J= 7.3 Hz, 2H), 2.86 (s, 6H).
    • Example 185: N-(3-Chloro-4-fluorophenyl)-2-(2-(diethylamino)ethyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0478
  • Example 185 was made analogously to Example 184 using diethylamine in place of dimethylamine. C19H22ClFN6O. 405.1 (M+1). 1H NMR (400 MHz, DMSO-d6 ) δ 11.08 (s, 1H), 8.91 (s, 1H), 8.30 (d, J = 5.1 Hz, 1H), 7.16 (d, J = 5.2 Hz, 1H), 7.04 (t, J = 9.1 Hz, 1H), 6.93 (dd, J = 6.5, 2.7 Hz, 1H), 6.50 (ddd, J = 9.0, 4.1, 2.7 Hz, 1H), 3.52 (t, J = 7.5 Hz, 2H), 3.28 (t, J = 7.5 Hz, 2H), 3.21 (q, J = 7.2 Hz, 4H), 1.22 (t, J = 7.2 Hz, 6H).
    • Example 186: N-(3-Chloro-4-fluorophenyl)-2-(2-((cyclopropylmethyl)(methyl)amino)ethyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0479
  • Example 186 was made analogously to Example 184 using 1-cyclopropyl-N-methylmethanamine in place of dimethylamine. C20H22ClFN6O. 417.1 (M+1). 1H NMR (400 MHz, DMSO-d6 ) δ 11.08 (s, 1H), 8.90 (s, 1H), 8.31 (d, J = 5.1 Hz, 1H), 7.17 (d, J = 5.1 Hz, 1H), 7.04 (t, J = 9.1 Hz, 1H), 6.93 (dd, J = 6.5, 2.7 Hz, 1H), 6.51 (ddd, J = 9.0, 4.1, 2.7 Hz, 1H), 3.59 (br s, 2H), 3.33 (t, J = 7.4 Hz, 2H), 3.10 (d, J = 7.3 Hz, 2H), 2.88 (s, 3H), 1.18-1.06 (m, 1H), 0.70-0.62 (m, 2H), 0.44-0.38 (m, 2H).
    • Example 187: N-(3-Chloro-4-fluorophenyl)-2-(2-((2,2-difluoroethyl)(methyl)amino)ethyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0480
  • A solution of 2-(7-(4-(3-chloro-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-l-(methylsulfonyl)-3H-imidazo[4,5-b]pyridin-2-yl)ethyl methanesulfonate (30 mg, 0.056 mmol) in acetonitrile (0.9 mL) was treated with N,N-diisopropylethylamine (0.20 mL, 1.1 mmol) followed by 2,2-difluoro-N-methylethanamine hydrochloride (148 mg, 1.13 mmol). The resulting solution was stirred for 2 h, then treated with dimethylamine (2.0 M solution in tetrahydrofuran, 0.5 mL, 1.0 mmol). After an additional 1 h of stirring, the mixture was treated with isopropylamine (0.2 mL, 2.3 mmol) and stirred for 20 min (in order to cleave the remaining imidazolyl methanesulfonyl group). The solution was then concentrated under reduced pressure and the resulting residue taken up in tetrahydrofuran (0.75 mL). The solution was treated with water (0.75 mL) followed by 2M sodium hydroxide (0.38 mL, 0.76 mmol), and stirred at room temperature for 20 min. An additional amount of 2M sodium hydroxide (0.75 mL, 1.5 mmol) was added, and stirring resumed for 15 min. Finally, the mixture was acidified with acetic acid, partially evaporated under reduced pressure, diluted with dimethyl sulfoxide, and purified by reverse phase preparative HPLC to provide the desired product. C18H18ClF3N6O. 427.1 (M+1).
    • Example 188: N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-(2-(methylamino)ethyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0481
  • A solution 2-(7-(4-(3-chloro-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-1-(methylsulfonyl)-1H-imidazo[4,5-b]pyridin-2-yl)ethyl methanesulfonate. (20 mg, 0.038mmol) and methylamine (2.0 M solution in tetrahydrofuran, 0.376mL, 0.752mmol) in acetonitrile (1 mL) was stirred for 2hr. The reaction was concentrated. The residue was brought up in tetrahydrofuran (0.5 mL) and water (0.5 mL). To this solution was added 2 N sodium hydroxide (0.22 mL, 0.43 mmol) and the reaction mixture stirred for 10 min. To the mixture was added acetic acid (0.035 mL) and the solution was loaded directly onto a prep HPLC for purification to give the desired product. C16H16ClFN6O. 363.11(M+1).
    • Example 189: 2-(2-Aminoethyl)-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0482
  • Example 189 was made analogously to Example 188 using ammonia (0.5 M solution in dioxane) in place of dimethylamine (2.0 M solution in tetrahydrofuran). C15H14ClFN6O. 349.1 (M+1).
    • Example 190: N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-(2-((2-methoxyethyl)amino)ethyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0483
  • Example 190 was made analogously to Example 188 using 2-methoxyethanamine in place of dimethylamine (2.0 M solution in tetrahydrofuran). C18H20ClFN6O2. 407.1 (M+1).
    • Example 191: N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-(2-morpholinoethyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0484
  • Example 191 was made analogously to Example 188 using morpholine in place of dimethylamine (2.0 M solution in tetrahydrofuran). C19H20ClFN6O2. 419.13 (M+1)
    • Example 192: N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-(2-(piperidin-1-yl)ethyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0485
  • Example 192 was made analogously to Example 184 using piperidine in place of dimethylamine. C20H22ClFN6O. 417.1 (M+1). 1H NMR (400 MHz, DMSO-d6 ) δ 11.10 (s, 1H), 8.90 (s, 1H), 8.30 (d, J = 5.1 Hz, 1H), 7.16 (d, J = 5.1 Hz, 1H), 7.04 (t, J = 9.1 Hz, 1H), 6.93 (dd, J = 6.5, 2.7 Hz, 1H), 6.52 (ddd, J = 9.0, 4.1, 2.8 Hz, 1H), 3.69-2.76 (m, 8H), 1.99-1.28 (m, 6H).
    • Example 193: N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-(2-(pyrrolidin-1-yl)ethyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0486
  • Example 193 was made analogously to Example 184 using pyrrolidine in place of dimethylamine. C19H20ClFN6O. 403.1 (M+1). 1H NMR (400 MHz, DMSO-d6 ) δ 11.10 (s, 1H), 8.89 (s, 1H), 8.31 (d, J = 5.1 Hz, 1H), 7.16 (d, J = 5.1 Hz, 1H), 7.04 (t, J = 9.1 Hz, 1H), 6.94 (dd, J = 6.6, 2.7 Hz, 1H), 6.51 (ddd, J = 9.0, 4.1, 2.7 Hz, 1H), 3.61 (t, J = 7.4 Hz, 2H), 3.57-2.99 (m, 6H), 1.96 (br s, 4H).
    • Example 194: N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-(2-((2-methoxyethyl)(methyl)amino)ethyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0487
  • Example 194 was made analogously to Example 187 using 2-methoxy-N-methylethanamine in place of 2,2-difluoro-N-methylethanamine hydrochloride and N,N-diisopropylethylamine. C19H22ClFN6O2. 421.1 (M+1). 1H NMR (400 MHz, DMSO-d6 ) δ 11.09 (s, 1H), 8.89 (s, 1H), 8.30 (d, J = 5.1 Hz, 1H), 7.15 (d, J= 5.1 Hz, 1H), 7.04 (t, J = 9.1 Hz, 1H), 6.93 (dd, J = 6.5, 2.7 Hz, 1H), 6.52 (ddd, J = 9.0, 4.1, 2.8 Hz, 1H), 3.70 (t, J = 5.0 Hz, 2H), 3.60 (t, J = 7.4 Hz, 2H), 3.40 (t, J = 5.1 Hz, 2H), 3.36-3.29 (m, 5H), 2.86 (s, 3H).
    • Example 195: N-(3-Chloro-4-fluorophenyl)-2-(2-(dimethylamino)-1-hydroxyethyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0488
  • N-(3-chloro-4-fluorophenyl)-2-(2,2-dimethyl-1,3-dioxolan-4-yl)-1H-imidazo[4,5-b]pyridine-7-carboxamide. A solution of 2,3-diamino-N-(3-chloro-4-fluorophenyl)isonicotinamide (3.00 g, 10.7 mmol) and 2,2-dimethyl-1,3-dioxolane-4-carbaldehyde (50% by weight in dichloromethane, 13.9 g, 53.4 mmol) in dimethyl sulfoxide (110 mL) was stirred vigorously under an air atmosphere at 100 °C overnight. The mixture was cooled to room temperature, diluted with water and brine solution, and extracted with dichloromethane (700 mL). The organic layer was then washed three times with water (500 mL), concentrated under reduced pressure, and adsorbed onto silica gel for purification by flash chromatography (0-70% EtOAc/hexanes) to provide the desired product. C18H16ClFN4O3. 391.1 (M+1).
    Figure imgb0489
  • N-(3-chloro-4-fluorophenyl)-2-(1,2-dihydroxyethyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide. A suspension of N-(3-chloro-4-fluorophenyl)-2-(2,2-dimethyl-1,3-dioxolan-4-yl)-1H-imidazo[4,5-b]pyridine-7-carboxamide (300 mg, 0.768 mmol) in methanol (38 mL) was treated with hydrogen chloride (4.0 M in dioxane, 1.5 mL, 6.0 mmol) and stirred at 70 °C overnight. The mixture was concentrated under reduced pressure to provide the desired product. C15H12ClFN4O3. 351.1 (M+1).
    Figure imgb0490
  • N-(3-chloro-4-fluorophenyl)-2-(2,2,3,3,8,8,9,9-octamethyl-4,7-dioxa-3,8-disiladecan-5-yl)-1H-imidazo[4,5-b]pyridine-7-carboxamide. A suspension of N-(3-chloro-4-fluorophenyl)-2-(1,2-dihydroxyethyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide (727 mg, 2.07 mmol) and 2,6-lutidine (3.9 mL, 33 mmol) in dichloromethane (41 mL) was cooled to 0 °C with stirring under a nitrogen atmosphere. The mixture was then treated with tert-butyldimethylsilyl trifluoromethanesulfonate (3.8 mL, 17 mmol) dropwise and with stirring. The mixture was then warmed to room temperature and stirred for 20 min, then adsorbed onto silica gel for purification by flash chromatography (0-40% EtOAc/hexanes) to provide the desired product. C27H40ClFN4O3Si2. 579.3 (M+1).
    Figure imgb0491
  • 2-(1-((tert-butyldimethylsilyl)oxy)-2-hydroxyethyl)-N-(3-chloro-4-fluorophenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide. A suspension of N-(3-chloro-4-fluorophenyl)-2-(2,2,3,3,8,8,9,9-octamethyl-4,7-dioxa-3,8-disiladecan-5-yl)-1H-imidazo[4,5-b]pyridine-7-carboxamide (200 mg, 0.345 mmol) in ethanol (7 mL) was treated with pyridinium p-tolueneslfonate (781 mg, 3.11 mmol) and stirred at 80 °C for 90 min. The mixture was then cooled to room temperature, diluted with saturated aqueous sodium bicarbonate, and extracted three times with ethyl acetate. The combined organic layers were adsorbed onto silica gel for purification by flash chromatography (20-55% EtOAc/hexanes) to provide the desired product. C21H26ClFN4O3Si. 365.3 (M+1).
    Figure imgb0492
  • 2-((tert-butyldimethylsilyl)oxy)-2-(7-((3-chloro-4-fluorophenyl)carbamoyl)-1-(methylsulfonyl)-1H-imidazo[4,5-b]pyridin-2-yl)ethyl methanesulfonate. A solution of 2-(1-((tert-butyldimethylsilyl)oxy)-2-hydroxyethyl)-N-(3-chloro-4-fluorophenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide (90 mg, 0.19 mmol) and N,N-diisopropylethylamine (0.74 mL, 1.9 mmol) in dichloromethane (3.9 mL) was cooled to 0 °C with stirring under a nitrogen atmosphere. The mixture was treated with methanesulfonyl chloride (0.075 mL, 0.97 mmol) dropwise and with stirring. After 5 min, the mixture was diluted with water, then extracted three times with dichloromethane. The combined organic layers were loaded onto a silica gel cartridge for purification by flash chromatography (0-100% EtOAc/hexanes) to provide the desired product. C23H30ClFN4O7S2Si. 621.2 (M+1).
    Figure imgb0493
  • 2-(1-((tert-butyldimethylsilyl)oxy)-2-(dimethylamino)ethyl)-N-(3-chloro-4-fluorophenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide. A solution of 2-((tert-butyldimethylsilyl)oxy)-2-(7-((3-chloro-4-fluorophenyl)carbamoyl)-1-(methylsulfonyl)-3H-imidazo[4,5-b]pyridin-2-yl)ethyl methanesulfonate (90 mg, 0.145 mmol) in acetonitrile (2.9 mL) was treated with dimethylamine (2.0 M in tetrahydrofuran, 2.90 mL, 5.80 mmol) and stirred at 60 °C for for 3 h. Additional dimethylamine (2.0 M in tetrahydrofuran, 1.0 mL, 2.0 mmol) was then added, and stirring at 60 °C resumed for 2 h. The mixture was then cooled to room temperature and concentrated under reduced pressure. Purification of the resulting residue by flash chromatography (0-30% MeOH/DCM) provided the desired product. C23H31ClFN5O2Si. 492.3 (M+1).
    Figure imgb0494
  • 2-(1-((tert-butyldimethylsilyl)oxy)-2-(dimethylamino)ethyl)-N-(3-chloro-4-fluorophenyl)-1H-imidazo[4,5-b]pyridine-7-carbothioamide was made analogously to Example 183 using 2-(1-((tert-butyldimethylsilyl)oxy)-2-(dimethylamino)ethyl)-N-(3-chloro-4-fluorophenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide in place of N-(3-chloro-4-fluorophenyl)-2-(2-((triisopropylsilyl)oxy)ethyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide. C23H31ClFN5OSSi. 508.2 (M+1).
    Figure imgb0495
  • N-(3-chloro-4-fluorophenyl)-2-(2-(dimethylamino)-1-hydroxyethyl)-1H-imidazo[4,5-b]pyridine-7-carbothioamide. A solution of 2-(1-((tert-butyldimethylsilyl)oxy)-2-(dimethylamino)ethyl)-N-(3-chloro-4-fluorophenyl)-1H-imidazo[4,5-b]pyridine-7-carbothioamide (59 mg, 0.12 mmol) and hydrogen chloride (4.0 M solution in dioxane, 0.226 mL, 0.906 mmol) in methanol (5.8 mL) was stirred at 80 °C for 24 h. The mixture was then cooled to room temperature, diluted with dimethyl sulfoxide, and purified by reverse phase preparative HPLC to provide the desired product. C17H17ClFN5OS. 594.2 (M+1).
    Figure imgb0496
  • N-(3-chloro-4-fluorophenyl)-2-(2-(dimethylamino)-1-hydroxyethyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide. A solution of N-(3-chloro-4-fluorophenyl)-2-(2-(dimethylamino)-1-hydroxyethyl)-1H-imidazo[4,5-b]pyridine-7-carbothioamide (5 mg, 0.013 mmol) and hydroxylamine (50% solution in water, 0.156 mL, 2.54 mmol) in methanol (1 mL) was stirred at 70 °C for 10 min. The mixture was then diluted with dimethyl sulfoxide and purified by reverse phase preparative HPLC to provide the desired product. C17H18ClFN6O2. 393.1 (M+1).
    • Example 196: N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-((isobutylamino)methyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0497
  • Example 196 was synthesized analogously to Example 112 using 3-(2-(bromomethyl)-1H-imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one and 2-methylpropan-1-amine in place of (7-(4-(3-chloro-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-1-(methylsulfonyl)-1H-imidazo[4,5-b]pyridin-2-yl)methyl methanesulfonate and morpholine, respectively. C18H20ClFN6O. 391.1 [M+1]+.
    • Example 197: N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-3-methyl-3H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0498
  • N,4-dimethyl-3-nitropyridin-2-amine. A solution of 4-methyl-3-nitro-2-chloropyridine (2.07 g, 12.0 mmol) and methylamine (40% in water, 7.2 mL, 84 mmol) in ethanol (14 mL) was stirred at 80 °C for 1.5 hr. The reaction was concentrated to give the desired product. C7H9N3O2. 168.0 (M+1).
    Figure imgb0499
  • 2-Methylamino-3-amino-4-methylpyridine. A mixture of N,4-dimethyl-3-nitropyridin-2-amine (2.01 g, 12.0 mmol) and 10% Paladium on Carbon (128 mg, 0.12 mmol) was mixed in a Parr Shaker at 40 psi hydrogen for 2 hr. The reaction mixture was filtered and concentrated to give the desired product. C7H11N3. 138.1 (M+1).
    Figure imgb0500
  • 3,7-Dimethyl-3H-imidazo[4,5-b]pyridine. A solution of 2-methylamino-3-amino-4-methylpyridine (830 mg, 6.05 mmol) in trimethylorthoformate (20 mL) was stirred at 100 °C for 3 hr and concentrated. The residue was purified by silica gel chromatography to give the desired product. C8H9N3. 148.0 (M+1).
    Figure imgb0501
  • 3-Methyl-3H-imidazo[4,5-b]pyridine-7-carboxylic acid. To a solution of 3,7-dimethyl-3H-imidazo[4,5-b]pyridine (726 mg, 4.93 mmol) sodium carbonate (523 mg, 4.93 mmol) in water (30 mL) at 100 C was added potassium permanganate (7.8 g, 49.2 mmol) in portions over two days. Na2CO3 and water are added to the starting material . The reaction mixture is heated until boiled, which caused a homogeneous solution. KMnO4 was added in small portions to the boiling solution. The reaction is stirred for another hour. LCMS shows low conversion. More KMnO4 was added in small batches at 100 °C for the next two days. The reaction mixture was filtered hot and the filtrate was acidified with 1 N HCl, concentrated and purified by prep HPLC to give the desired product. C8H7N3O2. 178.0 (M+1).
    Figure imgb0502
  • N-(3-chloro-4-fluorophenyl)-3-methyl-3H-imidazo[4,5-b]pyridine-7-carboxamide. A solution of 3-methyl-3H-imidazo[4,5-b]pyridine-7-carboxylic acid (100 mg, 0.564 mmol), hydroxybenzotriazole (173 mg, 1.13 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (216 mg, 1.13 mmol), and diisopropylethylamine (0.690 mL, 3.95 mmol) in dimethylformamide (2 mL) was stirred for 18 hr. To the reaction mixture was added saturated sodium bicarbonate Stirred all together overnight. Added saturated aqueous sodium bicarbonate and the resulting solid was filtered, triturated with 10% citric acid, filtered, and dried on high vac. C14H10ClFN4O. 305.1 (M+1).
    Figure imgb0503
  • N-(3-chloro-4-fluorophenyl)-N'-hydroxy-3-methyl-3H-imidazo[4,5-b]pyridine-7-carboximidamide. Example 197 was made analogously to Example 107 using N-(3-chloro-4-fluorophenyl)-3-methyl-3H-imidazo[4,5-b]pyridine-7-carboxamide in place of N-(3-Chloro-4-fluorophenyl)-2-methyl-1H-imidazo[4,5-b]pyridine-7-carboxamide. C14H11ClFN5O. 320.0 (M+1).
  • The following compounds were prepared according to the procedures described herein using the appropriate starting materials.
    • Example 198: N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-[2-(2-methoxyethytamino)ethyl]-3H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0504
    • Example 199: N-(3-Chloro-4-fluorophenyl)-2-[3-(dimethylamino)propyl]-6,7-difluoro-N'-hydroxy-3H-benzimidazole-4-carboximidamide
  • Figure imgb0505
    • Example 200: N-(3-Chloro-4-fluorophenyl)-7-fluoro-N'-hydroxy-2-(3-morpholin-4-ylpropylamino)-3H-benzimidazole-4-carboximidamide
  • Figure imgb0506
    • Example 201: N-(3-Chloro-4-fluorophenyl)-2-[2-(dimethylamino)ethylamino]-7-fluoro-N'-hydroxy-3H-benzimidazole-4-carboximidamide
  • Figure imgb0507
    • Example 202: N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-[(1-methylpiperidin-2-yl)methylamino]-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0508
    • Example 203: N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-[(1-methylpyrrolidin-3-yl)amino]-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0509
    • Example 204: N-(3-chloro-4-fluorophenyl)-2-(2-(ethylamino)ethyl)-N'-hydroxy-3H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0510
  • Example 204 was made analogously to Example 188 using ethylamine (2.0 M solution in tetrahydrofuran) in place of dimethylamine. C17H18ClFN6O. 377.1 (M+1).
    • Example 205: N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(2-(isopropylamino)ethyl)-3H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0511
  • Example 205 was made analogously to Example 188 using isopropylamine in place of dimethylamine. C18H20ClFN6O. 391.1 (M+1).
    • Example 206: N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(2-(isobutylamino)ethyl)-3H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0512
  • Example 206 was made analogously to Example 188 using isobutylamine in place of dimethylamine. C19H22ClFN6O. 405.1 (M+1).
    • Example 207: N-(3-chloro-4-fluorophenyl)-2-(2-(cyclopropylamino)ethyl)-N'-hydroxy-3H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0513
  • Example 207 was made analogously to Example 188 using cyclopropylamine in place of dimethylamine. C18H18ClFN6O. 389.1 (M+1).
    • Example 208: N-(3-chloro-4-fluorophenyl)-2-(2-((cyclopropylmethyl)amino)ethyl)-N-hydroxy-3H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0514
  • Example 208 was made analogously to Example 188 using cyclopropylmethanamine in place of dimethylamine. C19H20ClFN6O. 403.1 (M+1).
    • Example 209: 2-(2-(2-amino-4,5-dihydro-1H-imidazol-1-yl)ethyl)-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0515
  • Example 209 was made analogously to Example 188 using 4,5-dihydro-1H-imidazol-2-amine in place of dimethylamine. C18H18ClFN8O. 417.1 (M+1).
    • Example 210: N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-(2-(methylsulfonamido)ethyl)-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0516
  • Example 210 was made analogously to Example 112 using 2-(2-aminoethyl)-N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide in place of 4-(3-chloro-4-fluorophenyl)-3-(2-(hydroxymethyl)-1H-imidazo[4,5-b]pyridin-7-yl)-1,2,4-oxadiazol-5(4H)-one. C17H15ClF3N5O3S. 462.3 (M+1).
    • Example 211: 2-(2-aminoethyl)-N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0517
  • 2-(2-aminoethyl)-4,5-difluoro-1H-benzo[d]imidazole-7-carboxylic acid was made analogously to Example 53 using 3-aminopropanoic acid in place of 3-(dimethylamino)propanoic acid. C10H9F2N3O2. 241.1(M+1).
    Figure imgb0518
  • To a mixture of 2-(2-aminoethyl)-4,5-difluoro-1H-benzo[d]imidazole-7-carboxylic acid (2g, 8.29 mmol) in THF (30mL) and sat. sodium bicarbonate solution 30mL was added di-tertbutyldicarbonate (7.24g, 33mmol). Stirred for 72 h. Acidified with 4N HCl and brought the pH to ∼1. The reaction mixture was extracted with ethyl acetate (50mL x 3). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography to give 2-(2-((tert-butoxycarbonyl)amino)ethyl)-4,5-difluoro-1H-benzo[d]imidazole-7-carboxylic acid. C15H17F2N3O4. 342.1 (M+1).
    Figure imgb0519
  • tert-butyl (2-(7-((3-chloro-4-fluorophenyl)carbamoyl)-4,5-difluoro-1H-benzo[d]imidazol-2-yl)ethyl)carbamate was made analogously to Example 53 using 2-(2-((tertbutoxycarbonyl)amino)ethyl)-4,5-difluoro-1H-benzo[d]imidazole-7-carboxylic acid in place of 2-(2-(dimethylamino)ethyl)-6,7-difluoro-1Hbenzo[d]imidazole-4-carboxylic. 469.12 (M+1). C21H20ClF3N4O3. 469.12 (M+1).
    Figure imgb0520
  • 2-(2-aminoethyl)-N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide was made analogously to Example 53 using tert-butyl (2-(7-((3-chloro-4-fluorophenyl)carbamoyl)-4,5-difluoro-1H-benzo[d]imidazol-2-yl)ethyl)carbamate in place of N-(3-chloro-4-fluorophenyl)-2-(2-(dimethylamino)ethyl)-4,5-difluoro-1H-benzo[d]imidazole-7-carboxamide. C16H13ClF3N5O. 384.2 (M+1).
    • Example 212: N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((2-methoxyethyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0521
  • A 500mL round bottom flask equipped with a stir bar was charged with 2,3-diamino-N-(3-chloro-4-fluorophenyl)isonicotinamide (34g, 121.1 mmol) and 1,1'-carbonyldiimidazole (CDI) (29.5g, 181.7mmol) followed by THF (300mL). The reaction mixture was stirred at room temperature for 16hr. THF 150mL was removed under reduced pressure. Water 250mL was then slowly added to the reaction mixture. Reaction mixture was then stirred for 1 hour, and precipitate was isolated via vacuum filtration and washed with water (100mL x 3). The solid was dried in a vacuum oven at 40 °C overnight to afford a light red solid (34g, 110.8 mmol) and used in the next step without further purification. C13H8ClFN4O2. 307.2 (M+1).
    Figure imgb0522
  • N-(3-chloro-4-fluorophenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine-7-carboxamide (5.0g, 16.3 mmol) was dissolved in POCl3 (33 eq., 538 mmol, 82.5 mL) and PCl5 (3 eq., 48.9 mmol, 10.19 g) was added. The reaction was sealed in a glass vessel and heated to 100 °C for 16 hours. The reaction was allowed to cool to room temperature and then transferred to a round bottom flask. The POCl3 was removed under reduced pressure and the residue was taken up in 100 mL of p-dioxane. In a separate round bottom flask, NH2OH (50% in water, 92.8 eq, 1.52 mol, 100 mL) was added to 200 mL p-dioxane and cooled to ∼3 °C in an ice bath with continuous stirring. The crude imidoyl chloride in p-dioxane mixture was added very slowly to the hydroxylamine mixture (over ∼45 mins, dropwise) while maintaining the hydroxylamine/dioxane solution ∼3 °C. Once the addition was complete, the reaction was allowed to slowly come to room temperature and stirred for 20 mins. The reaction was then diluted with EtOAc (500 mL), sat. sodium bicarbonate solution (300 mL), and brine (150 mL) and allowed to stir for an additional 20 mins. The reaction was extracted and the organic layer was washed once with brine (200 mL), dried over Na2SO4, filtered, and concentrated to dryness to give crude 2-chloro-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide which was used in the next step without further purification. C13H8Cl2FN5O. 340.1 (M+1).
  • Crude 2-chloro-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide from previous step (5.5 g, 16.31 mmol assumed 100% yield from starting N-(3-chloro-4-fluorophenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine-7-carboxamide) was dissolved in ethyl acetate (80 mL, C=0.2 M) and 1,1'-carbonyldiimidazole (CDI) (2 eq, 5.3 g, 32.6 mmol) was added. The reaction was allowed to stir at room temperature (capped but under air) for 1 hour until no SM was seen by LCMS. The reaction was then carefully diluted with water (80 mL, some gas evolution seen) and the reaction was allowed to stir for 10 mins before being poured into a separatory funnel (∼15 mL of brine added to help break up emulsions) and the organic layer was extracted. The organic layer was washed once more with water (∼50mL with ∼10mL brine) and the organic layer was then concentrated. The crude was wet loaded on to silica gel and purified by column chromatography (Rf 0.75 in 100% EtOAc, column run 40-100% EtOAc/hex) to give 3-(2-chloro-1H-imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one as a pale yellow solid. C14H6Cl2FN5O2. 365.9 (M+1).
    Figure imgb0523
  • 3-(2-chloro-1H-imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one (804 mg, 2.2 mmol) was weighed into a round bottom flask which was then evacuated and purged twice with argon. CH2Cl2 (30.0 mL, C=0.075 M) was added via syringe and the reaction was cooled to 0 °C in an ice bath. Hunig's base (2.5 eq, 5.49 mmol, 0.956 mL) was added followed by SEM-Cl (2.3 eq, 5.051 mmol, 0.894 mL) (added dropwise). The reaction was allowed to stir at 0 °C for 20 mins until no starting material was seen by LCMS. The reaction was then poured into DI water (40 mL) in a separatory funnel and then shaken. The organic layer was removed and concentrated under reduced pressure. The crude was wet loaded on to a silica gel column and purified by normal phase column chromatography (20-80% EtOAc/hex, Rf= 0.42 in 40% EtOAc/hex) to give 3-(2-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one as a pale yellow oil which solidified upon standing.
    Figure imgb0524
  • 3-(2-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one (0.015g, 0.03mmol) was dissolved in DMSO (0.5 ml), and 2-methoxyethanamine (4.54mg, 0.060 mmol) was added to the solution. The reaction mixture was heated at 60°C for 2h. The mixture was cooled to rt and partitioned between sat. bicarb solution (1 mL) and EtOAc (2 mL) and the aqueous layer was extracted 1× with EtOAc (1 mL). The combined organic layers were washed with sat. bicarb solution (1 mL). Organic layers were then concentrated and taken up in DCM (1.6mL) and trifluoroacetic acid (0.4 mL). The reaction mixture was stirred for 1h and concentrated. The residue was brought up in tetrahydrofuran (0.5 mL). To this solution was added 2 N sodium hydroxide solution (0.22 mL, 0.44 mmol) and the reaction mixture stirred for 30 min. To the mixture was added acetic acid (0.10 mL), DMSO (2 mL) and water (2mL), the solution was loaded directly onto a prep HPLC for purification to give the desired product. C16H16ClFN6O2.379.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 11.72 (s, 1H), 11.43 (s, 1H), 8.95 (s, 1H), 7.97 (d, J = 6.3 Hz, 1H), 7.11 (t, J = 9.0 Hz, 1H), 7.04 (dd, J = 6.5, 2.7 Hz, 1H), 6.93 (d, J = 6.3 Hz, 1H), 6.60 (ddd, J = 9.0, 4.0, 2.8 Hz, 1H), 3.61 (t, J = 5.3 Hz, 2H), 3.53 (t, J = 5.1 Hz, 2H), 3.30 (s, 3H).
    • Example 213: tert-butyl (2-(7-(N-(3-chloro-4-fluorophenyl)-N'-hydroxycarbamimidoyl)-4,5-difluoro-1H-benzo[d]imidazol-2-yl)ethyl)carbamate
  • Figure imgb0525
  • Example 213 was made analogously to Example 211 using 2-(2-aminoethyl)-N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide in place of 2-(2-aminoethyl)-4,5-difluoro-1H-benzo[d]imidazole-7-carboxylic acid. C21H21ClF3N5O3. 484.4 (M+1).
    • Example 214: N-(3-chloro-4-fluorophenyl)-2-((2-(4,4-difluoropiperidin-1-yl)ethyl)amino)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0526
  • Example 214 was made analogously to Example 212 using 2-(4,4-difluoropiperidin-1-yl)ethanamine in place of 2-methoxyethanamine. C20H21ClF3N7O. 468.88 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 8.94 (s, 1H), 7.96 (d, J = 5.8 Hz, 1H), 7.09 (t, J = 9.0 Hz, 1H), 6.98 (s, 1H), 6.91 (d, J = 6.0 Hz, 1H), 6.55 (dt, J = 8.9, 3.5 Hz, 1H), 3.33 (m, 8H), 2.33 - 2.18 (m, 4H).
    • Example 215: N-(3-chloro-4-fluorophenyl)-2-((2-(dimethylamino)ethyl)amino)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0527
  • Example 215 was made analogously to Example 212 using N1,N1-dimethylethane-1,2-diamine in place of 2-methoxyethanamine. C17H19ClFN7O. 392.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 8.93 (s, 1H), 7.94 (s, 1H), 7.08 (t, J = 9.1 Hz, 1H), 6.96 (s, 1H), 6.89 (d, J = 5.9 Hz, 1H), 6.54 (d, J = 8.6 Hz, 1H), 3.73 (s, 2H), 3.31 (s, 2H), 2.85 (s, 6H).
    • Example 216: N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((2-(methylamino)ethyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0528
  • Example 216 was made analogously to Example 212 using tert-butyl (2-aminoethyl)(methyl)carbamate in place of 2-methoxyethanamine. C16H17ClFN7O. 378.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 8.94 (s, 1H), 8.57 (s, 2H), 7.95 (d, J = 6.0 Hz, 1H), 7.09 (t, J = 9.0 Hz, 1H), 6.97 (s, 1H), 6.90 (d, J = 6.2 Hz, 1H), 6.59 - 6.47 (m, 1H), 3.67 (s, 2H), 3.16 (s, 2H), 2.61 (s, 3H).
    • Example 217: N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((1-methylazepan-3-yl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0529
  • Example 217 was made analogously to Example 212 using 1-methylazepan-3-amine in place of 2-methoxyethanamine. C20H23ClFN7O. 432.2 (M+1). 1H NMR (400 MHz, DMSO-d 6) δ 8.92 (s, 1H), 7.96 (s, 1H), 7.09 (t, J = 9.0 Hz, 1H), 6.97 (s, 1H), 6.90 (d, J = 6.1 Hz, 1H), 6.55 (s, 1H), 4.25 (s, 1H), 3.6 - 3.3 (m, 3H), 3.18 (s, 2H), 2.87 (s, 3H), 2.13 - 1.41 (m, 6H).
    • Example 218: N-(3-chloro-4-fluorophenyl)-2-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0530
  • Example 218 was made analogously to Example 212 using 4-(2-aminoethyl)thiomorpholine 1,1-dioxide in place of 2-methoxyethanamine. C19H21ClFN7O3S. 482.1 (M+1). 1H NMR (400 MHz, DMSO-d 6) δ 11.40 (s, 1H), 8.97 (s, 1H), 7.96 (d, J = 6.4 Hz, 1H), 7.09 (t, J = 9.0 Hz, 1H), 7.02 (dd, J = 6.5, 2.7 Hz, 1H), 6.91 (d, J = 6.2 Hz, 1H), 6.61 - 6.52 (m, 1H), 3.55 (d, J = 5.9 Hz, 2H), 3.12 (s, 5H), 3.06 (s, 5H), 2.81 (s, 2H).
    • Example 219: N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((2-((2-methoxyethyl)(methyl)amino)ethyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0531
  • Example 219 was made analogously to Example 212 using N1-(2-methoxyethyl)-N1-methylethane-1,2-diamine in place of 2-methoxyethanamine. C19H23ClFN7O2. 427.03 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 11.36 (s, 1H), 8.96 (s, 1H), 7.97 (d, J = 6.2 Hz, 1H), 7.09 (t, J = 9.0 Hz, 1H), 6.98 (d, J = 6.4 Hz, 1H), 6.93 (d, J = 6.2 Hz, 1H), 6.55 (ddd, J = 9.0, 4.0, 2.8 Hz, 1H), 3.78 (s, 2H), 3.64 (t, J = 5.0 Hz, 2H), 3.37 (s, 4H), 3.24 (s, 3H), 2.86 (s, 3H).
    • Example 220: N-(3-chloro-4-fluorophenyl)-2-((2-((2,2-difluoroethyl)(methyl)amino)ethyl)amino)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0532
  • Example 220 was made analogously to Example 212 using N 1-(2,2-difluoroethyl)-N 1-methylethane-1,2-diamine in place of 2-methoxyethanamine. C18H19ClF3N7O. 442.1 (M+1). 1HNMR (400 MHz, DMSO-d6) δ 11.40 (s, 1H), 8.96 (s, 1H), 7.96 (d, J = 6.3 Hz, 1H), 7.09 (t, J = 9.0 Hz, 1H), 7.01 (dd, J = 6.5, 2.8 Hz, 1H), 6.92 (d, J = 6.2 Hz, 1H), 6.56 (ddd, J = 8.9, 3.9, 2.7 Hz, 1H), 6.25 (t, J = 55.0 Hz, 1H), 3.62 (d, J = 6.5 Hz, 2H), 3.18 (s, 2H), 2.97 (s, 2H), 2.57 (s, 2H).
    • Example 221: N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((3-morpholinopropyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0533
  • Example 221 was made analogously to Example 212 using 3-morpholinylpropan-1-amine in place of 2-methoxyethanamine. C20H23ClFN7O2. 448.2 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 11.38 (s, 1H), 8.96 (s, 1H), 7.97 (d, J = 6.2 Hz, 1H), 7.09 (t, J = 9.0 Hz, 1H), 7.01 (dd, J = 6.5, 2.7 Hz, 1H), 6.92 (d, J = 6.2 Hz, 1H), 6.60 - 6.52 (m, 1H), 4.2-3.55 (m, 8H), 3.49 (d, J = 6.5 Hz, 2H), 3.15 (t, J = 8.0 Hz, 2H), 1.98 (d, J = 8.0 Hz, 2H).
    • Example 222: N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((2-(piperidin-1-yl)ethyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0534
  • Example 222 was made analogously to Example 212 using 2-(piperidin-1-yl)ethanamine in place of 2-methoxyethanamine. C20H23ClFN7O.432.2 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 8.94 (s, 1H), 7.96 (d, J = 6.2 Hz, 1H), 7.09 (t, J = 9.1 Hz, 1H), 6.98 (d, J = 6.3 Hz, 1H), 6.91 (d, J = 6.0 Hz, 1H), 6.60 - 6.51 (m, 1H), 3.74 (M, 4H), 3.28 (d, J = 7.0 Hz, 2H), 1.73 (s, 5H), 1.54 (s, 3H).
    • Example 223: N-(3-chloro-4-fluorophenyl)-2-((2-cyclohexylethyl)amino)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0535
  • Example 223 was made analogously to Example 212 using 2-(3-fluoropiperidin-1-yl)ethanamine in place of 2-methoxyethanamine. C21H24ClFN6O. 431.2 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 11.37 (s, 1H), 8.94 (s, 1H), 7.93 (s, 1H), 7.08 (t, J = 9.0 Hz, 1H), 7.02 (m, 1H), 6.90 (s, 1H), 6.56 (d, J = 9.0 Hz, 1H), 1.68 (m, 6H), 1.46 (d, J = 7.7 Hz, 2H), 1.30 (s, 1H), 1.16 (m, 3H), 0.90 m, 3H).
    • Example 224: N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((2-(tetrahydro-2H-pyran-4-yl)ethyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0536
  • Example 224 was made analogously to Example 212 using 2-(tetrahydro-2H-pyran-4-yl)ethanamine in place of 2-methoxyethanamine. C20H22ClFN6O2. 433.2 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 11.36 (s, 1H), 8.95 (s, 1H), 7.94 (d, J = 6.2 Hz, 1H), 7.08 (t, J = 9.1 Hz, 1H), 7.04 - 6.99 (m, 1H), 6.90 (d, J = 6.1 Hz, 1H), 6.60 - 6.51 (m, 1H), 3.82 (dd, J = 11.0, 4.2 Hz, 2H), 3.26 (d, J = 12.0 Hz, 2H), 1.62 - 1.43 (m, 7H), 1.17 (d, J = 12.6 Hz, 2H).
    • Example 225: N-(3-chloro-4-fluorophenyl)-2-((2,2-difluoroethyl)amino)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0537
  • Example 225 was made analogously to Example 212 using 2,2-difluoroethanamine in place of 2-methoxyethanamine. C15H12ClF3N6O. 385.1 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 11.46 (s, 1H), 8.98 (s, 1H), 7.08 (t, J = 9.0 Hz, 1H), 7.03 (dd, J = 6.5, 2.7 Hz, 1H), 6.93 (d, J = 6.3 Hz, 1H), 6.62 - 6.52 (m, 1H), 6.22 (t, J = 55.3 Hz, 1H), 3.87 (d, J = 16.8 Hz, 2H).
    • Example 226: N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(oxetan-3-ylamino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0538
  • Example 226 was made analogously to Example 212 using oxetan-3-amine in place of 2-methoxyethanamine. C16H14ClFN6O2. 377.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 8.88 (s, 1H), 7.96 (s, 1H), 7.06 (t, J = 9.1 Hz, 1H), 7.01 (d, J = 5.4 Hz, 1H), 6.96 (d, J = 6.5 Hz, 1H), 6.54 (ddd, J = 9.0, 4.1, 2.8 Hz, 1H), 4.57 (s, 1H), 4.32 (t, J = 9.8 Hz, 1H), 4.05 (s, 1H), 3.58 (s, 2H).
    • Example 227: N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((tetrahydrofuran-3-yl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0539
  • Example 227 was made analogously to Example 212 using tetrahydrofuran-3-amine in place of 2-methoxyethanamine. C17H16ClFN6O2. 391.1 (M+1). 1H NMR(400 MHz, DMSO-d6) δ 11.40 (s, 1H), 8.94 (s, 1H), 8.50 (s, 1H), 7.96 (d, J = 6.3 Hz, 1H), 7.09 (t, J = 9.0 Hz, 1H), 7.02 (dd, J = 6.5, 2.7 Hz, 1H), 6.92 (d, J = 6.3 Hz, 1H), 6.57 (ddd, J = 8.9, 4.0, 2.8 Hz, 1H), 4.44 (q, J = 5.8, 3.7 Hz, 1H), 3.93 - 3.78 (m, 2H), 3.74 (td, J = 8.4, 5.3 Hz, 1H), 3.69 (d, 1H), 2.30-2.18 (m, 1H), 1.90 (dd, J = 14.8, 7.7 Hz, 1H).
    • Example 228: N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((tetrahydro-2H-pyran-4-yl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0540
  • Example 228 was made analogously to Example 212 using tetrahydro-2H-pyran-4-amine in place of 2-methoxyethanamine. C18H18ClFN6O2. 405.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 11.43 (s, 1H), 8.97 (s, 1H), 7.97 (d, J = 6.3 Hz, 1H), 7.10 (t, J = 9.1 Hz, 1H), 7.06 (dd, J = 6.7, 2.9 Hz, 1H), 6.94 (d, J = 6.3 Hz, 1H), 6.58 (dt, J = 8.9, 3.4 Hz, 1H), 4.04-3.86 (m, 3H), 3.41 (td, J = 11.7, 2.1 Hz, 2H), 1.87 (d, J = 12.5 Hz, 2H), 1.70 - 1.48 (m, 2H).
    • Example 229: 3-((7-(N-(3-chloro-4-fluorophenyl)-N'-hydroxycarbamimidoyl)-4,5-difluoro-1H-benzo[d]imidazol-2-yl)amino)propanamide)
  • Figure imgb0541
  • A mixture of 3-(2-chloro-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one (0.025 g, 0.047 mmol), 3-aminopropanamide hydrochloride (0.023 g, 0.188 mmol) and DIPEA (0.05 mL, 0.282 mmol) in DMSO (0.5 mL) stirred at 60 °C for 16 h. The mixture was cooled to rt, diluted with water, and extracted 3× with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated. The resulting residue was brought up in DCM (0.5 mL) and TFA (0.5 mL) and stirred for 16 h. The reaction solution was concentrated. The resulting residue was brought up in THF (0.5 mL) and water (0.5 mL) and sodium hydroxide (0.76 mL of a 2 N solution, 1.5 mmol). The resulting solution was stirred for 10 min, acidified with AcOH (0.10 mL, 1.8 mmol), and purified by preparative HPLC to give the desired product (0.009 g). C17H14ClF3N6O2. 427.0 (M+1).
    • Example 230: N-(3-chloro-4-fluorophenyl)-2-((2-((2,2-difluoroethyl)amino)ethyl)amino)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0542
  • Example 230 was made analogously to Example 229 using N1-(2,2-difluoroethyl)ethane-1,2-diamine hydrochloride in place of 3-aminopropanamide hydrochloride. C17H17ClF3N7O. 428.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 11.28 (s, 1H), 8.91 (s, 1H), 7.95 (d, J = 6.1 Hz, 1H), 7.09 (t, J = 9.0 Hz, 1H), 6.97 (dd, J = 6.6, 2.7 Hz, 1H), 6.90 (d, J = 6.1 Hz, 1H), 6.56 (ddd, J = 9.0, 4.0, 2.7 Hz, 1H), 6.53 - 6.21 (m, 1H), 3.8 - 3.3 (m, 5H) 3.26 (t, J = 5.9 Hz, 2H).
    • Example 231: N-(3-chloro-4-fluorophenyl)-2-((2-(cyclopropyl(methyl)amino)ethyl)amino)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0543
  • Example 231 was made analogously to Example 212 using N 1-cyclopropyl-N 1-methylethane-1,2-diamine in place of 2-methoxyethanamine. C19H21ClFN7O. 418.2 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 11.27 (s, 1H), 8.92 (s, 1H), 7.95 (d, J = 6.0 Hz, 1H), 7.83 (s, 1H), 7.08 (t, J = 9.1 Hz, 1H), 6.97 (d, J = 6.4 Hz, 1H), 6.91 (d, J = 6.0 Hz, 1H), 6.55 (ddd, J = 9.0, 4.0, 2.8 Hz, 1H), 3.76 (s, 3H), 2.90 (s, 3H), 1.02 - 0.66 (m, 5H).
    • Example 232: N-(3-chloro-4-fluorophenyl)-2-((2-(cyclopropyl(2-methoxyethyl)amino)ethyl)amino)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0544
  • Example 232 was made analogously to Example 212 using N 1-cyclopropyl-N 1-(2-methoxyethyl)ethane-1,2-diamine in place of 2-methoxyethanamine. C21H25ClFN7O2. 462.2 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 11.32 (s, 1H), 8.93 (s, 1H), 7.96 (d, J = 6.1 Hz, 1H), 7.08 (t, J = 9.0 Hz, 1H), 7.02 - 6.89 (m, 2H), 6.56 (ddd, J = 8.9, 4.0, 2.7 Hz, 1H), 3.76 (s, 4H), 3.65 (d, J = 5.1 Hz, 1H), 3.37 (s, 4H), 3.26 (s, 3H), 0.79 (s, 4H).
    • Example 233: 2-((2-(azetidin-1-yl)ethyl)amino)-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0545
  • Example 233 was made analogously to Example 212 using 22-(azetidin-1-yl)ethanamine in place of 2-methoxyethanamine. C18H19ClFN7O. 404.2 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 11.31 (s, 1H), 9.92 (s, 1H), 8.92 (s, 1H), 7.96 (d, J = 6.1 Hz, 1H), 7.08 (t, J = 9.0 Hz, 1H), 6.98 (dd, J = 6.6, 2.7 Hz, 1H), 6.93 (d, J = 6.1 Hz, 1H), 6.55 (ddd, J = 9.0, 4.0, 2.7 Hz, 1H), 4.10 (d, J = 8.9 Hz, 4H), 3.38 (s, 4H), 2.32 (d, J = 6.7 Hz, 2H).
    • Example 234: N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((3-methoxypropyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0546
  • Example 234 was made analogously to Example 212 using 3-methoxypropan-1-amine in place of 2-methoxyethanamine. C17H18ClFN6O2. 427.03 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 11.89 (s, 1H), 11.39 (s, 1H), 8.95 (s, 1H), 7.96 (d, J = 6.2 Hz, 1H), 7.10 (t, J = 9.0 Hz, 1H), 7.04 (dd, J = 6.5, 2.7 Hz, 1H), 6.92 (d, J = 6.2 Hz, 1H), 6.59 (ddd, J = 9.0, 4.0, 2.8 Hz, 1H), 3.49 (q, J = 6.6 Hz, 2H), 3.41 (t, J = 6.0 Hz, 2H), 3.25 (s, 3H), 1.83 (p, J = 6.5 Hz, 2H).
    • Example 235: N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((2-(2-oxopyrrolidin-1-yl)ethyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0547
  • Example 235 was made analogously to Example 212 using 1-(2-aminoethyl)pyrrolidin-2-one in place of 2-methoxyethanamine. C19H19ClFN7O2. 432.2 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 11.99 (s, 1H), 11.43 (s, 1H), 8.97 (s, 1H), 7.98 (d, J = 6.3 Hz, 1H), 7.10 (t, J = 9.0 Hz, 1H), 7.04 (dd, J = 6.5, 2.8 Hz, 1H), 6.96 (d, J = 6.3 Hz, 1H), 6.58 (ddd, J = 8.9, 4.0, 2.8 Hz, 1H), 3.59 (q, J = 6.0 Hz, 2H), 3.41 (dt, J = 14.1, 6.5 Hz, 4H), 2.17 (dd, J = 8.7, 7.5 Hz, 2H), 2.01 - 1.73 (m, 2H).
    • Example 236: N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((2-(morpholinosulfonyl)ethyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0548
  • Example 236 was made analogously to Example 212 using 2-(morpholinosulfonyl)ethanamine in place of 2-methoxyethanamine. C19H21ClFN7O4S. 498.2 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 11.45 (s, 1H), 8.96 (s, 1H), 7.97 (d, J = 6.4 Hz, 1H), 7.09 (t, J = 9.0 Hz, 1H), 7.02 (dd, J = 6.5, 2.7 Hz, 1H), 6.93 (d, J = 6.4 Hz, 1H), 6.57 (ddd, J = 9.0, 4.0, 2.8 Hz, 1H), 3.86 (q, J = 6.5 Hz, 2H), 3.68 - 3.58 (m, 4H), 3.43 (t, J = 6.7 Hz, 2H), 3.21 - 3.09 (m, 4H).
    • Example 237: N-(3-chloro-4-fluorophenyl)-2-((2-(3-fluoropiperidin-1-yl)ethyl)amino)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0549
  • Example 237 was made analogously to Example 212 using 2-(3-fluoropiperidin-1-yl)ethanamine TFA salt in place of 2-methoxyethanamine. C20H22ClF2N7O. 450.2 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 11.33 (s, 1H), 8.95 (s, 1H), 7.99 (d, J = 6.1 Hz, 1H), 7.11 (t, J = 9.1 Hz, 1H), 7.01 (dd, J = 6.5, 2.8 Hz, 1H), 6.94 (d, J = 6.1 Hz, 1H), 6.58 (ddd, J = 8.9, 4.0, 2.7 Hz, 1H), 5.09 (d, J = 44.9 Hz, 1H), 3.88 - 3.73 (m, 2H), 3.43 (s, 2H), 3.35 (s, 2H), 3.11 (s, 2H), 2.03 - 1.66 (m, 4H).
    • Example 238: N-(3-bromo-4-fluorophenyl)-N'-hydroxy-2-((2-morpholinoethyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0550
  • Example 238 was made analogously to Example 212 using 4-(3-bromo-4-fluorophenyl)-3-(2-chloro-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridin-7-yl)-1,2,4-oxadiazol-5(4H)-one and 2-morpholinoethanamine in place of 3-(2-chloro-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one and 2-methoxyethanamine, respectively. C19H21BrFN7O2. 478.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 11.30 (s, 1H), 8.92 (s, 1H), 7.97 (d, J = 6.1 Hz, 1H), 7.12 (dd, J = 6.1, 2.7 Hz, 1H), 7.05 (t, J = 8.7 Hz, 1H), 6.92 (d, J = 6.1 Hz, 1H), 6.58 (ddd, J = 8.9, 4.1, 2.7 Hz, 1H), 3.80 (m, 6H), 3.33 (s, 6H).
    • Example 239: N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((2-(methyl(tetrahydro-2H-pyran-4-yl)amino)ethyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0551
  • Example 239 was made analogously to Example 212 using N1-methyl-N1-(tetrahydro-2H-pyran-4-yl)ethane-1,2-diamine in place of 2-methoxyethanamine. C21H25ClFN7O2. 462.2 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 8.91 (s, 1H), 7.08 (t, J = 9.1 Hz, 1H), 6.95 (s, 1H), 6.90 (d, J = 6.0 Hz, 1H), 6.54 (dt, J = 9.0, 3.4 Hz, 1H), 3.94 (d, J = 11.8 Hz, 2H), 3.31 (d, J = 12.1 Hz, 3H), 2.82 (s, 3H), 1.87 (d, J = 13.4 Hz, 2H), 1.65 (dd, J = 12.0, 4.6 Hz, 2H).
    • Example 240: N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((2-(isopropyl(methyl)amino)ethyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0552
  • Example 240 was made analogously to Example 212 using N1-isopropyl-N1-methylethane-1,2-diamine in place of 2-methoxyethanamine. C19H23ClFN7O. 420.2 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 11.28 (s, 1H), 8.91 (s, 1H), 7.95 (d, J = 5.9 Hz, 1H), 7.84 (s, 1H), 7.08 (t, J = 9.0 Hz, 1H), 6.96 (s, 1H), 6.90 (d, J = 6.0 Hz, 1H), 6.54 (dt, J = 8.8, 3.5 Hz, 1H), 3.74 (s, 2H), 3.69 - 3.59 (m, 1H), 3.27 (s, 2H), 2.76 (s, 3H), 1.20 (d, J = 6.6 Hz, 6H).
    • Example 241: 2-(((1-aminocyclopropyl)methyl)amino)-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0553
  • Example 241 was made analogously to Example 212 using tert-butyl (1-(aminomethyl)cyclopropyl)carbamate in place of 2-methoxyethanamine. C17H17ClFN7O. 390.2 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 11.34 (s, 1H), 8.92 (s, 1H), 8.34 (s, 3H), 7.95 (d, J = 6.1 Hz, 1H), 7.09 (t, J = 9.0 Hz, 1H), 6.98 (dd, J = 6.5, 2.7 Hz, 1H), 6.91 (d, J = 6.2 Hz, 1H), 6.56 (ddd, J = 9.0, 4.0, 2.8 Hz, 1H), 3.68 (s, 2H), 0.92 (d, J = 5.5 Hz, 4H).
    • Example 242: 2-((2-(1-aminocyclopropyl)ethyl)amino)-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0554
  • Example 242 was made analogously to Example 212 using tert-butyl (1-(2-aminoethyl)cyclopropyl)carbamate in place of 2-methoxyethanamine. C18H19ClFN7O. 404.2 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 11.33 (s, 1H), 8.93 (s, 1H), 8.20 (s, 3H), 7.95 (d, J = 6.2 Hz, 1H), 7.08 (t, J = 9.0 Hz, 1H), 6.99 (dd, J = 6.5, 2.7 Hz, 1H), 6.93 (d, J = 6.1 Hz, 1H), 6.61 - 6.50 (m, 1H), 3.57 (t, 2H), 1.89 (t, J = 7.0 Hz, 2H), 0.81 (d, J = 6.9 Hz, 2H), 0.69 (d, J = 5.9 Hz, 2H).
    • Example 243: 2-((2-(2-oxa-5-azabicyclo[4.1.0]heptan-5-yl)ethyl)amino)-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0555
  • tert-butyl (2-(2-oxa-5-azabicyclo[4.1.0]heptan-5-yl)ethyl)carbamate. A mixture of tert-butyl (2-bromoethyl)carbamate (0.500 g, 3.688 mmol), 2-oxa-5-azabicyclo[4.1.0]heptane hydrochloride (0.826 g, 3.688 mmol) and DIPEA (1.285 mL, 7.375 mmol) in DMSO (4 mL) was stirred at 40 °C for 16 h. The mixture was diluted with sat NaHCO3 soln. The aqueous layer was extracted 3× with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated. The residue was purified via silica gel chromatography to give the desired product (0.440 g). C12H22N2O3. 243.1 (M+1).
    Figure imgb0556
  • 2-(2-oxa-5-azabicyclo[4.1.0]heptan-5-yl)ethanamine hydrochloride. To a solution of tert-butyl (2-(2-oxa-5-azabicyclo[4.1.0]heptan-5-yl)ethyl)carbamate (0.08 g, 0.33 mmol) in THF was added HCl (2.0 mL of a 4 M soln in dioxane, 8 mmol). The mixture stirred at rt for 16 h. The mixture was concentrated to give the desired product as the HCl salt (0.071 g). C7H16N2O. 143.1 (M+1).
    Figure imgb0557
  • Example 243 was made analogously to Example 229 using 3-(2-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one and 2-(2-oxa-5-azabicyclo[4.1.0]heptan-5-yl)ethanamine hydrochloride in place of 3-(2-chloro-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one and 3-aminopropanamide hydrochloride, respectively. C20H21ClFN7O2. 446.2 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 11.35 (s, 1H), 8.96 (s, 1H), 7.96 (d, J = 6.2 Hz, 1H), 7.09 (t, J = 9.0 Hz, 1H), 7.00 (dd, J = 6.5, 2.7 Hz, 1H), 6.92 (d, J = 6.2 Hz, 1H), 6.56 (dt, J = 9.0, 3.4 Hz, 1H), 3.80-3.63 (m, 4H), 3.53 (t, J = 11.5 Hz, 2H), 3.18 (s, 2H), 2.96 - 2.60 (m, 2H), 0.90 (d, J = 149.8 Hz, 2H).
    • Example 244: 2-((2-(7-oxa-4-azaspiro[2.5]octan-4-yl)ethyl)amino)-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0558
  • tert-butyl (2-(7-oxa-4-azaspiro[2.5]octan-4-yl)ethyl)carbamate was prepared analogously to Example 243 using 7-oxa-4-azaspiro[2.5]octane hydrochloride in place of 2-oxa-5-azabicyclo[4.1.0]heptane hydrochloride. C14H16N2O2. 245.1 (M+1).
    Figure imgb0559
  • 2-(7-oxa-4-azaspiro[2.5]octan-4-yl)ethanamine hydrochloride was prepared analogously to Example 243using tert-butyl (2-(7-oxa-4-azaspiro[2.5]octan-4-yl)ethyl)carbamate in place of tert-butyl (2-(2-oxa-5-azabicyclo[4.1.0]heptan-5-yl)ethyl)carbamate. C8H16N2O. 157.1 (M+1).
    Figure imgb0560
  • Example 244 was made analogously to Example 229 using 2-(7-oxa-4-azaspiro[2.5]octan-4-yl)ethanamine in place of 3-aminopropanamide hydrochloride. C21H23ClFN7O2. 460.2 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 11.34 (s, 1H), 8.96 (s, 1H), 7.97 (d, J = 6.1 Hz, 1H), 7.09 (t, J = 9.0 Hz, 1H), 6.98 (d, J = 6.0 Hz, 1H), 6.93 (d, J = 6.1 Hz, 1H), 6.56 (dt, J = 8.8, 3.7 Hz, 1H), 4.2-3.00 (m, 10H), 1.20 - 0.34 (m, 4H).
    • Example 245: (R)-(3-chloro-4-fluorophenyl)-2-((2-(3-fluoropyrrolidin-1-yl)ethyl)amino)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0561
  • (R)-tert-butyl (2-(3-fluoropyrrolidin-1-yl)ethyl)carbamate was prepared analogously to Example 242 using (R)-3-fluoropyrrolidine hydrochloride in place of 2-oxa-5-azabicyclo[4.1.0]heptane hydrochloride. C11H21FN2O2. 233.2 (M+1).
    Figure imgb0562
  • (R)-2-(3-fluoropyrrolidin-1-yl)ethanamine hydrochloride was prepared analogously to Example 242 using (R)-tert-butyl (2-(3-fluoropyrrolidin-1-yl)ethyl)carbamate in place of tert-butyl (2-(2-oxa-5-azabicyclo[4.1.0]heptan-5-yl)ethyl)carbamate. C6H13FN2. 133.1 (M+1).
    Figure imgb0563
  • Example 245 was made analogously to Example 229 using (R)-2-(3-fluoropyrrolidin-1-yl)ethanamine hydrochloride in place of 3-aminopropanamide hydrochloride. C19H20ClF2N7O. 436.2(M+1). 1H NMR (400 MHz, DMSO-d6) δ 11.34 (s, 1H), 8.95 (s, 1H), 7.96 (d, J = 6.2 Hz, 1H), 7.09 (t, J = 9.0 Hz, 1H), 6.98 (dd, J = 6.3, 2.7 Hz, 1H), 6.92 (d, J = 6.1 Hz, 1H), 6.55 (ddd, J = 8.9, 4.0, 2.7 Hz, 1H), 5.48 (d, J = 53.2 Hz, 1H), 3.90 - 3.35 (m, 8H), 2.43 - 2.09 (m, 2H).
    • Example 246: (S)-(3-chloro-4-fluorophenyl)-2-((2-(3-fluoropyrrolidin-1-yl)ethyl)amino)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0564
  • (S)-tert-butyl (2-(3-fluoropyrrolidin-1-yl)ethyl)carbamate was prepared analogously to Example 243 using (S)-3-fluoropyrrolidine hydrochloride in place of 2-oxa-5-azabicyclo[4.1.0]heptane hydrochloride. C11H21FN2O2. 233.2 (M+1).
    Figure imgb0565
  • (S)-2-(3-fluoropyrrolidin-1-yl)ethanamine hydrochloride was prepared analogously to Example 242 using (S)-tert-butyl (2-(3-fluoropyrrolidin-1-yl)ethyl)carbamate in place of tert-butyl (2-(2-oxa-5-azabicyclo[4.1.0]heptan-5-yl)ethyl)carbamate. C6H13FN2. 133.1 (M+1).
    Figure imgb0566
  • Example 246 was made analogously to Example 229 using (S)-2-(3-fluoropyrrolidin-1-yl)ethanamine hydrochloride in place of 3-aminopropanamide hydrochloride. C19H20ClF2N7O. 436.2 (M+1) 1H NMR (400 MHz, DMSO-d6) δ 11.35 (s, 1H), 8.95 (s, 1H), 7.97 (d, J = 6.2 Hz, 1H), 7.09 (t, J = 9.0 Hz, 1H), 6.99 (dd, J = 6.5, 2.7 Hz, 1H), 6.92 (d, J = 6.2 Hz, 1H), 6.55 (ddd, J = 9.0, 4.0, 2.8 Hz, 1H), 5.48 (d, J = 53.1 Hz, 1H), 3.90 - 3.35 (m, 8H), 2.44 - 2.11 (m, 2H).
    • Example 247: 2-((2-(2-azabicyclo[4.1.0]heptan-2-yl)ethyl)amino)-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0567
  • tert-butyl (2-(2-azabicyclo[4.1.0]heptan-2-yl)ethyl)carbamate was prepared analogously to Example 243 using (2-azabicyclo[4.1.0]heptane in place of 2-oxa-5-azabicyclo[4.1.0]heptane hydrochloride. C13H24N2O2. 241.3 (M+1).
    Figure imgb0568
  • 2-(2-azabicyclo[4.1.0]heptan-2-yl)ethanamine hydrochloride was prepared analogously to Example 243 using tert-butyl (2-(2-azabicyclo[4.1.0]heptan-2-yl)ethyl)carbamate in place of tert-butyl (2-(2-oxa-5-azabicyclo[4.1.0]heptan-5-yl)ethyl)carbamate. C8H16N2. 141.3 (M+1).
    Figure imgb0569
  • Example 247 was made analogously to Example 229 using 2-(2-azabicyclo[4.1.0]heptan-2-yl)ethanamine hydrochloride in place of 3-aminopropanamide hydrochloride. C21H23ClFN7O. 444.2 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 11.36 (s, 1H), 8.96 (s, 1H), 8.08 (s, 1H), 7.97 (d, J = 6.2 Hz, 1H), 7.09 (t, J = 9.0 Hz, 1H), 6.99 (dd, J = 6.5, 2.7 Hz, 1H), 6.93 (d, J = 6.2 Hz, 1H), 6.55 (ddd, J = 9.0, 4.1, 2.8 Hz, 1H), 3.90 - 3.30 (m, 5H), 3.12 (s, 1H), 3.01 (s, 1H), 2.90 (d, J = 19.4 Hz, 1H), 1.98 (d, J = 10.9 Hz, 1H), 1.54 (s, 2H), 1.43 - 1.28 (m, 1H), 1.00 - 0.91 (m, 1H), 0.91 - 0.81 (m, 1H).
    • Example 248: 2-((2-(4-azaspiro[2.5]octan-4-yl)ethyl)amino)-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0570
  • Example 248 was prepared analogously to Example 243 using 4-azaspiro[2.5]octane hydrochloride in place of 2-oxa-5-azabicyclo[4.1.0]heptane hydrochloride. C14H26N2O2. 255.3 (M+1).
    Figure imgb0571
  • 2-(4-azaspiro[2.5]octan-4-yl)ethanamine hydrochloride was prepared analogously to Example 243 using tert-butyl (2-(4-azaspiro[2.5]octan-4-yl)ethyl)carbamate in place of tert-butyl (2-(2-oxa-5-azabicyclo[4.1.0]heptan-5-yl)ethyl)carbamate. C9H18N2. 155.3 (M+1).
    Figure imgb0572
  • Example 248 was made analogously to Example 229 using 2-(4-azaspiro[2.5]octan-4-yl)ethanamine hydrochloride in place of 3-aminopropanamide hydrochloride. C22H25ClFN7O. 458.2 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 11.31 (s, 1H), 8.95 (s, 1H), 7.97 (d, J = 6.0 Hz, 1H), 7.78 (s, 1H), 7.08 (t, J = 9.0 Hz, 1H), 6.96 (s, 1H), 6.92 (d, J = 6.0 Hz, 1H), 6.54 (dt, J = 9.0, 3.5 Hz, 1H), 3.8-3.3 (m, 8H), 1.80 (s, 2H), 1.65 (s, 2H), 1.04 (s, 2H), 0.76 (s, 2H).
    • Example 249: N-(3-chloro-4-fluorophenyl)-2-((2-(3-fluoroazetidin-1-yl)ethyl)amino)- N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0573
  • tert-butyl (2-(3-fluoroazetidin-1-yl)ethyl)carbamate was prepared analogously to Example 243 using 3-fluoroazetidine hydrochloride in place of 2-oxa-5-azabicyclo[4.1.0]heptane hydrochloride. C10H26FN2O2. 218.2 (M+1).
    Figure imgb0574
  • 2-(3-fluoroazetidin-1-yl)ethanamine hydrochloride was prepared analogously to Example 243 using tert-butyl (2-(3-fluoroazetidin-1-yl)ethyl)carbamate in place of tert-butyl (2-(2-oxa-5-azabicyclo[4.1.0]heptan-5-yl)ethyl)carbamate. C9H18N2. 119.1 (M+1).
    Figure imgb0575
  • Example 249 was made analogously to Example 229 using 2-(3-fluoroazetidin-1-yl)ethanamine hydrochloride in place of 3-aminopropanamide hydrochloride. C18H18ClF2N7O. 422.2 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 11.95 (s, 1H), 11.34 (s, 1H), 8.94 (s, 1H), 7.97 (d, J = 6.2 Hz, 1H), 7.08 (t, J = 9.0 Hz, 1H), 6.98 (dd, J = 6.4, 2.7 Hz, 1H), 6.92 (d, J = 6.2 Hz, 1H), 6.55 (ddd, J = 9.0, 4.1, 2.7 Hz, 1H), 5.45 - 5.30 (m, 1H), 4.52 (dd, J = 20.6, 12.4, 5.9 Hz, 2H), 4.33 (dd, J = 22.1, 12.2 Hz, 2H), 3.63 (s, 2H), 3.48 (s, 2H).
    • Example 250: N-(3-chloro-4-fluorophenyl)-2-((2-(3,3-difluoroazetidin-1-yl)ethyl)amino)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0576
  • tert-butyl (2-(3,3-difluoroazetidin-1-yl)ethyl)carbamate was prepared analogously to Example 243 using 3,3-difluoroazetidine hydrochloride in place of 2-oxa-5-azabicyclo[4.1.0]heptane hydrochloride. C10H18F2N2O2. 237.2 (M+1).
    Figure imgb0577
  • 2-(3,3-difluoroazetidin-1-yl)ethanamine hydrochloride was prepared analogously to Example 243 using tert-butyl (2-(3,3-difluoroazetidin-1-yl)ethyl)carbamate in place of tert-butyl (2-(2-oxa-5-azabicyclo[4.1.0]heptan-5-yl)ethyl)carbamate. C5H10F2N2. 137.1 (M+1).
    Figure imgb0578
  • Example 250 was made analogously to Example 229 using 2-(3,3-difluoroazetidin-1-yl)ethanamine hydrochloride in place of 3-aminopropanamide hydrochloride. C18H17ClF3N7O. 440.2 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 11.41 (s, 1H), 8.96 (s, 1H), 7.97 (d, J = 6.3 Hz, 1H), 7.09 (t, J = 9.0 Hz, 1H), 7.01 (dd, J = 6.5, 2.7 Hz, 1H), 6.93 (d, J = 6.3 Hz, 1H), 6.56 (ddd, J = 9.0, 4.0, 2.8 Hz, 1H), 4.09 (s, 4H), 3.54 (s, 2H), 3.07 (s, 2H).
    • Example 251: 2-((2-(4-azaspiro[2.4]heptan-4-yl)ethyl)amino)-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0579
  • tert-butyl (2-(4-azaspiro[2.4]heptan-4-yl)ethyl)carbamate was prepared analogously to Example 244 using 4-azaspiro[2.4]heptane hydrochloride in place of 2-oxa-5-azabicyclo[4.1.0]heptane hydrochloride. C13H24N2O2. 241.2 (M+1).
    Figure imgb0580
  • 2-(4-azaspiro[2.4]heptan-4-yl)ethanamine hydrochloride was prepared analogously to Example 243 using tert-butyl (2-(4-azaspiro[2.4]heptan-4-yl)ethyl)carbamate in place of tert-butyl (2-(2-oxa-5-azabicyclo[4.1.0]heptan-5-yl)ethyl)carbamate. C8H16N2. 141.1 (M+1).
    Figure imgb0581
  • Example 251 was made analogously to Example 229 using 2-(4-azaspiro[2.4]heptan-4-yl)ethanamine hydrochloride in place of 3-aminopropanamide hydrochloride. C21H23ClFN7O. 444.2 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 11.33 (s, 1H), 8.95 (s, 1H), 7.97 (d, J = 6.1 Hz, 1H), 7.08 (t, J = 9.0 Hz, 1H), 6.98 (d, J = 6.4 Hz, 1H), 6.93 (d, J = 6.1 Hz, 1H), 6.55 (ddd, J = 8.9, 4.0, 2.7 Hz, 1H), 3.65 -3.75 (m, 4H), 3.17 (t, J = 6.0 Hz, 2H), 2.17 - 1.92 (m, 4H), 1.22 (t, 2H), 0.84 (t, 2H).
    • Example 252: N-(3-chloro-4-fluorophenyl)-2-((3-(3-fluoropiperidin-1-yl)propyl)amino)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0582
  • tert-butyl (3-(3-fluoropiperidin-1-yl)propyl)carbamate was prepared analogously to Example 243 using 3-fluoropiperidine hydrochloride in place of 2-oxa-5-azabicyclo[4.1.0]heptane hydrochloride. C13H25FN2O2. 261.2 (M+1).
    Figure imgb0583
  • 3-(3-fluoropiperidin-1-yl)propan-1-amine hydrochloride was prepared analogously to Example 243 using tert-butyl (3-(3-fluoropiperidin-1-yl)propyl)carbamate in place of tert-butyl (2-(2-oxa-5-azabicyclo[4.1.0]heptan-5-yl)ethyl)carbamate. C8H17FN2. 161.1 (M+1).
    Figure imgb0584
  • Example 252 was made analogously to Example 229 using 3-(3-fluoropiperidin-1-yl)propan-1-amine hydrochloride in place of 3-aminopropanamide hydrochloride. C21H24ClF2N7O.464.2 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 12.07 (s, 1H), 11.38 (s, 1H), 8.96 (s, 1H), 8.22 (d, J = 58.7 Hz, 1H), 7.97 (d, J = 6.2 Hz, 1H), 7.09 (t, J = 9.0 Hz, 1H), 7.01 (dd, J = 6.5, 2.7 Hz, 1H), 6.93 (d, J = 6.2 Hz, 1H), 6.56 (ddd, J = 9.0, 4.0, 2.8 Hz, 1H), 5.08 (d, J = 45.5 Hz, 1H), 3.47 (d, J = 6.4 Hz, 1H), 3.35 (s, 3H), 3.12 (q, J = 7.4 Hz, 2H), 3.02 (s, 2H), 2.08 - 1.84 (m, 4H), 1.75 (d, J = 14.5 Hz, 2H).
    • Example 253: N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((2-(phenylamino)ethyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0585
  • Example 253 was made analogously to Example 212 using N 1-phenylethane-1,2-diamine in place of 2-methoxyethanamine. C21H19ClFN7O. 440.2 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 11.42 (s, 1H), 8.96 (s, 1H), 7.95 (d, J = 6.3 Hz, 1H), 7.14 - 7.04 (m, 4H), 7.02 (dd, J = 6.5, 2.8 Hz, 1H), 6.90 (d, J = 6.3 Hz, 1H), 6.65 - 6.50 (m, 4H), 3.62 (d, J = 6.0 Hz, 2H), 3.28 (t, J = 6.3 Hz, 2H).
    • Example 254: N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((2-(methyl(phenyl)amino)ethyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0586
  • Example 254 was made analogously to Example 212 using N 1-methyl-N 1-phenylethane-1,2-diamine in place of 2-methoxyethanamine. C22H21ClFN7O. 454.2 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 11.95 (s, 1H), 11.42 (s, 1H), 8.97 (s, 1H), 7.95 (d, J = 6.4 Hz, 1H), 7.19 - 7.12 (m, 2H), 7.09 (t, J = 9.0 Hz, 1H), 7.03 (dd, J = 6.5, 2.7 Hz, 1H), 6.92 (d, J = 6.3 Hz, 1H), 6.75 (d, J = 8.1 Hz, 2H), 6.61 (tt, J = 7.3, 1.0 Hz, 1H), 6.56 (ddd, J = 9.0, 4.0, 2.8 Hz, 1H), 3.64 (M, 4H), 2.89 (s, 3H).
    • Example 255: N-(3-chloro-4-fluorophenyl)-2-(((1,1-dioxidotetrahydro-2H-thiopyran-3-yl)methyl)amino)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0587
  • Example 255 was made analogously to Example 212 using 3-(aminomethyl)tetrahydro-2H-thiopyran 1,1-dioxide in place of 2-methoxyethanamine. C19H20ClFN6O3S. 467.2 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 11.41 (s, 1H), 8.96 (s, 1H), 7.95 (d, J = 6.3 Hz, 1H), 7.09 (t, J = 9.0 Hz, 1H), 7.03 (dd, J = 6.5, 2.7 Hz, 1H), 6.92 (d, J = 6.3 Hz, 1H), 6.57 (ddd, J = 9.0, 4.0, 2.8 Hz, 1H), 3.06 (m, 2H), 3.00 - 2.87 (m, 1H), 2.31 (m, 2H), 2.06 (dd, J = 10.3, 3.9 Hz, 2H), 1.76 (d, J = 13.6 Hz, 2H), 1.24 (q, J = 12.4 Hz, 2H).
    • Example 256: N-(3-chloro-4-fluorophenyl)-2-((2-ethoxycyclopropyl)amino)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0588
  • Example 256 was made analogously to Example 212 using 2-methoxycyclopropanamine in place of 2-methoxyethanamine. C18H18ClFN6O2. 405.2 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 11.34 (s, 1H), 8.95 (s, 1H), 7.98 (d, J = 6.3 Hz, 1H), 7.07 (t, J = 9.1 Hz, 1H), 7.02 (d, J = 5.5 Hz, 1H), 6.94 (d, J = 6.2 Hz, 1H), 6.55 (ddd, J = 8.9, 4.0, 2.8 Hz, 1H), 3.67 - 3.51 (m, 2H), 2.88 (s, 1H), 1.13 (t, J = 7.0 Hz, 3H), 1.11 - 1. 04 (m, 2H), 0.83 (s, 1H).
    • Example 257: N-(3-bromo-4-fluorophenyl)-N'-hydroxy-2-(methylamino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0589
  • Example 257 was made analogously to Example 212 using 4-(3-bromo-4-fluorophenyl)-3-(2-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-7-yl)-1,2,4-oxadiazol-5(4H)-one and methylamine (2.0 M solution in tetrahydrofuran) in place of 3-(2-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one and 2-methoxyethanamine, respectively. C14H12BrFN6O. 379.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 12.12 (s, 1H), 11.38 (s, 1H), 8.95 (s, 1H), 7.97 (d, J = 6.2 Hz, 1H), 7.16 (dd, J = 6.1, 2.7 Hz, 1H), 7.04 (t, J = 8.8 Hz, 1H), 6.92 (d, J = 6.2 Hz, 1H), 6.58 (ddd, J = 8.9, 4.1, 2.7 Hz, 1H), 3.00 (d, J = 4.7 Hz, 3H).
    • Example 258: 2-(2-(azepan-1-yl)ethyl)-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0590
  • Example 258 was made analogously to Example 184 using hexamethyleneimine in place of dimethylamine. C21H24ClFN6O. 431.2 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 11.09 (s, 1H), 8.90 (s, 1H), 8.30 (d, J = 5.1 Hz, 1H), 7.16 (d, J = 5.1 Hz, 1H), 7.04 (t, J = 9.1 Hz, 1H), 6.93 (dd, J = 6.5, 2.7 Hz, 1H), 6.51 (ddd, J = 9.0, 4.1, 2.8 Hz, 1H), 3.58 (t, J = 7.5 Hz, 2H), 3.45 - 3.22 (m, 6H), 1.90 - 1.74 (m, 4H), 1.69 - 1.57 (m, 4H).
    • Example 259: 2-(2-(azetidin-1-yl)ethyl)-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0591
  • Example 259 was made analogously to Example 184 using azetidine hydrochloride and N,N-diisopropylethylamine in place of dimethylamine. C18H18ClFN6O. 389.1 (M+1).
    • Example 260: (R)-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(2-(3-hydroxypyrrolidin-1-yl)ethyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0592
  • Example 260 was made analogously to Example 184 using (R)-pyrrolidin-3-ol in place of dimethylamine. C19H20ClFN6O2. 419.1 (M+1).
    • Example 261: (S)-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(2-(3-hydroxypyrrolidin-1-yl)ethyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0593
  • Example 261 was made analogously to Example 184 using (S)-pyrrolidin-3-ol hydrochloride and N,N-diisopropylethylamine in place of dimethylamine. C19H20ClFN6O2. 419.1 (M+1).
    • Example 262: N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(2-(4-hydroxypiperidin-1-yl)ethyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0594
  • Example 262 was made analogously to Example 184 using 4-hydroxypiperidine in place of dimethylamine. C20H22ClFN6O2. 433.1 (M+1).
    • Example 263: N-(3-bromo-4-fluorophenyl)-2-(2-(dimethylamino)ethyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0595
  • Ethyl 2-(7-((3-bromo-4-fluorophenyl)carbamoyl)-1H-imidazo[4,5-b]pyridin-2-yl)acetate was made analogously to Example 183 using 2,3-diamino-N-(3-bromo-4-fluorophenyl)isonicotinamide in place of 2,3-diamino-N-(3-chloro-4-fluorophenyl)isonicotinamide. C17H14BrFN4O3. 421.2, 423.1 (M+1).
    Figure imgb0596
  • N-(3-bromo-4-fluorophenyl)-2-(2-hydroxyethyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide was made analogously to Example 184 using ethyl 2-(7-((3-bromo-4-fluorophenyl)carbamoyl)-1H-imidazo[4,5-b]pyridin-2-yl)acetate in place of ethyl 2-(7-((3-chloro-4-fluorophenyl)carbamoyl)-1H-imidazo[4,5-b]pyridin-2-yl)acetate. C15H12BrFN4O2. 379.0, 381.0 (M+1).
    Figure imgb0597
  • N-(3-bromo-4-fluorophenyl)-2-(2-(dimethylamino)ethyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide was made analogously to Example 184 using N-(3-bromo-4-fluorophenyl)-2-(2-hydroxyethyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide in place of N-(3-chloro-4-fluorophenyl)-2-(2-hydroxyethyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide. C17Hl17BrFN5O. 406.1, 408.1 (M+1).
    Figure imgb0598
  • N-(3-bromo-4-fluorophenyl)-2-(2-(dimethylamino)ethyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide. Example XX was made analogously to Example 184 using N-(3-bromo-4-fluorophenyl)-2-(2-(dimethylamino)ethyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide in place of N-(3-chloro-4-fluorophenyl)-2-(2-(dimethylamino)ethyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide. C17H18BrFN6O. 421.0, 423.0 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 10.99 (s, 1H), 8.86 (s, 1H), 8.27 (dd, J = 5.0, 0.5 Hz, 1H), 7.13 (d, J = 5.1 Hz, 1H), 7.07 (dd, J = 6.1, 2.7 Hz, 1H), 6.99 (t, J = 8.8 Hz, 1H), 6.53 (ddd, J = 9.0, 4.1, 2.8 Hz, 1H), 3.38 - 3.18 (m, 4H), 2.69 (s, 6H).
    • Example 264: N-(3-chlorophenyl)-2-(2-(dimethylamino)ethyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0599
  • Ethyl 2-(7-((3-chlorophenyl)carbamoyl)-1H-imidazo[4,5-b]pyridin-2-yl)acetate was made analogously to Example 183 using 2,3-diamino-N-(3-chlorophenyl)isonicotinamide in place of 2,3-diamino-N-(3-chloro-4-fluorophenyl)isonicotinamide. C17H15ClN4O3. 359.3 (M+1).
    Figure imgb0600
  • N-(3-chlorophenyl)-2-(2-hydroxyethyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide was made analogously to Example 184 using ethyl 2-(7-((3-chlorophenyl)carbamoyl)-1H-imidazo[4,5-b]pyridin-2-yl)acetate in place of ethyl 2-(7-((3-chloro-4-fluorophenyl)carbamoyl)-1H-imidazo[4,5-b]pyridin-2-yl)acetate. C15H13ClN4O2. 317.1 (M+1).
    Figure imgb0601
  • N-(3-chlorophenyl)-2-(2-(dimethylamino)ethyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide was made analogously to Example 184 using N-(3-chlorophenyl)-2-(2-hydroxyethyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide in place of N-(3-chloro-4-fluorophenyl)-2-(2-hydroxyethyl)-1H -imidazo[4,5-b]pyridine-7-carboxamide. C17H18ClN5O. 344.3 (M+1).
    Figure imgb0602
  • N-(3-chlorophenyl)-2-(2-(dimethylamino)ethyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide was made analogously to Example 184 using N-(3-chlorophenyl)-2-(2-(dimethylamino)ethyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide in place of N-(3-chloro-4-fluorophenyl)-2-(2-(dimethylamino)ethyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide. C17H19ClN6O. 359.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 12.49 (s, 1H), 11.10 (s, 1H), 8.86 (s, 1H), 8.22 (d, J = 5.2 Hz, 1H), 7.08 (d, J = 5.0 Hz, 1H), 6.97 (t, J = 8.0 Hz, 1H), 6.83 (t, J = 2.1 Hz, 1H), 6.77 (dd, J = 7.8, 1.9 Hz, 1H), 6.44 (dd, J = 8.1, 2.1 Hz, 1H), 2.93 (t, J = 7.3 Hz, 2H), 2.61 (t, J = 7.3 Hz, 2H), 2.16 (s, 6H).
    • Example 265: N-(3-bromophenyl)-2-(2-(dimethylamino)ethyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0603
  • Ethyl 2-(7-((3-bromophenyl)carbamoyl)-1H-imidazo[4,5-b]pyridin-2-yl)acetate was made analogously to Example using 2,3-diamino-N-(3-bromophenyl)isonicotinamide in place of 2,3-diamino-N-(3-chloro-4-fluorophenyl)isonicotinamide. C17H15BrN4O3. 403.3, 405.2 (M+1).
    Figure imgb0604
  • N-(3-bromophenyl)-2-(2-hydroxyethyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide was made analogously to Example 184 using ethyl 2-(7-((3-bromophenyl)carbamoyl)-1H-imidazo[4,5-b]pyridin-2-yl)acetate in place of ethyl 2-(7-((3-chloro-4-fluorophenyl)carbamoyl)-1H-imidazo[4,5-b]pyridin-2-yl)acetate. C15H13BrN4O2. 361.0, 363.0 (M+1).
    Figure imgb0605
  • N-(3-bromophenyl)-2-(2-(dimethylamino)ethyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide was made analogously to Example 184 using N-(3-bromophenyl)-2-(2-hydroxyethyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide in place of N-(3-chloro-4-fluorophenyl)-2-(2-hydroxyethyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide. C17H18BrN5O. 388.2, 390.2 (M+1).
    Figure imgb0606
  • N-(3-bromophenyl)-2-(2-(dimethylamino)ethyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide. Example 266 was made analogously to Example 184 using N-(3-bromophenyl)-2-(2-(dimethylamino)ethyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide in place of N-(3-chloro-4-fluorophenyl)-2-(2-(dimethylamino)ethyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide. C17H19BrN6O. 403.0, 405.0 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 11.05 (s, 1H), 8.85 (s, 1H), 8.23 (dd, J = 5.1, 0.5 Hz, 1H), 7.09 (d, J = 5.1 Hz, 1H), 7.00 - 6.97 (m, 1H), 6.93 - 6.87 (m, 2H), 6.50 - 6.45 (m, 1H), 2.95 (t, J = 7.3 Hz, 2H), 2.69 - 2.62 (m, 2H), 2.19 (s, 6H).
    • Example 266: N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(2-(methylsulfonamido)ethyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0607
  • N-(2-(7-(4-(3-chloro-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-1-(methylsulfonyl)-1H-imidazo[4,5-b]pyridin-2-yl)ethyl)-N-(2,4-dimethoxybenzyl)methanesulfonamide. A solution of 4-(3-chloro-4-fluorophenyl)-3-(2-(2-((2,4-dimethoxybenzyl)amino)ethyl)-1H-imidazo[4,5-b]pyridin-7-yl)-1,2,4-oxadiazol-5(4H)-one (15 mg, 0.029 mmol) and pyridine (0.046 mL, 0.57 mmol) in dichloromethane (1.0 mL) was cooled in an ice bath with stirring and treated with methanesulfonyl chloride (0.022 mL, 0.29 mmol). The reaction mixture was then allowed to warm to room temperature. After 35 min, another portion of methanesulfonyl chloride (0.022 mL, 0.29 mmol) was added, followed 15 min later by further treatment with pyridine (0.023 mL, 0.29 mmol). After another 15 min, the reaction appeared to have stalled (based on LCMS analysis), with added reagents having no effect, so N,N-diisopropylethylamine (0.10 mL, 0.57 mmol) was added, resulting in complete conversion within 15 min. The reaction mixture was concentrated under reduced pressure, and loaded directly onto a silica gel cartridge for purification by flash chromatography (0-20% methanol/dichloromethane) to afford the desired product (20 mg) C27H26ClFN6O8S2. 681.0 (M+1).
    Figure imgb0608
  • N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(2-(methylsulfonamido)ethyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide. A solution of N-(2-(7-(4-(3-chloro-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-1-(methylsulfonyl)-1H-imidazo[4,5-b]pyridin-2-yl)ethyl)-N-(2,4-dimethoxybenzyl)methanesulfonamide (20 mg, 0.029 mmol) and triethylsilane (0.023 mL, 0.15 mmol) in dichloromethane (1 mL) was treated with trifluoroacetic acid (1 mL), and the reaction mixture was stirred overnight at room temperature. The mixture was then concentrated under reduced pressure and taken up in tetrahydrofuran (0.75 mL) and water (0.75 mL), and treated with a 2M aqueous solution of sodium hydroxide (0.75 mL, 1.5 mmol). After 15 min of stirring at room temperature, the reaction mixture was acidified with acetic acid, diluted with dimethyl sulfoxide, and purified by reverse phase preparative HPLC to provide the desired product (7 mg). C16H16ClFN6O3S. 427.0 (M+1).
    • Example 267: N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(2-(sulfamoylamino)ethyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0609
  • A suspension of 4-(3-chloro-4-fluorophenyl)-3-(2-(2-((2,4-dimethoxybenzyl)amino)ethyl)-1H-imidazo[4,5-b]pyridin-7-yl)-1,2,4-oxadiazol-5(4H)-one (15 mg, 0.029 mmol) and sulfamide (27 mg, 0.29 mmol) in pyridine (1 mL) was stirred at 120 °C for 20 min. The mixture was then cooled to room temperature and concentrated under reduced pressure. The resulting residue was suspended in dichloromethane (0.5 mL) and treated with triethylsilane (0.022 mL, 0.14 mmol) followed by trifluoroacetic acid (0.5 mL). After stirring at room temperature for 1 h, the reaction mixture was concentrated under reduced pressure and taken up in tetrahydrofuran (0.75 mL) and water (0.75 mL), and treated with a 2M aqueous solution of sodium hydroxide (0.75 mL, 1.5 mmol). After 15 min, another portion of 2M sodium hydroxide (1 mL, 2 mmol) was added, and the reaction was stirred for an additional 15 min. The mixture was then acidified with acetic acid, diluted with dimethyl sulfoxide, and purified by reverse phase preparative HPLC to provide the desired product (7 mg). C15H15ClFN7O3S. 428.0 (M+1).
    • Example 268: N-(3-chlorophenyl)-N'-hydroxy-2-(2-(pyrrolidin-1-yl)ethyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0610
  • N-(3-chlorophenyl)-2-(2-(pyrrolidin-1-yl)ethyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide was made analogously to Example 184 using N-(3-chlorophenyl)-2-(2-hydroxyethyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide in place of N-(3-chloro-4-fluorophenyl)-2-(2-hydroxyethyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide and pyrrolidine in place of dimethylamine. C19H20ClN5O. 370.1 (M+1).
    Figure imgb0611
  • N-(3-chlorophenyl)-N'-hydroxy-2-(2-(pyrrolidin-1-yl)ethyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide was made analogously to Example using N-(3-chlorophenyl)-2-(2-(pyrrolidin-1-yl)ethyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide in place of N-(3-chloro-4-fluorophenyl)-2-(2-(dimethylamino)ethyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide. C19H21ClN6O. 385.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 8.90 (s, 1H), 8.26 (dd, J = 5.1, 0.6 Hz, 1H), 7.11 (d, J = 5.0 Hz, 1H), 6.98 (t, J = 8.0 Hz, 1H), 6.84 - 6.76 (m, 2H), 6.46 (dd, J = 8.1, 2.1 Hz, 1H), 3.50 - 2.84 (m, 8H), 1.87 (s, 4H).
    • Example 269: N-(3-bromophenyl)-N'-hydroxy-2-(2-(pyrrolidin-1-yl)ethyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0612
  • N-(3-bromophenyl)-2-(2-(pyrrolidin-1-yl)ethyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide was made analogously to Example 184 using N-(3-bromophenyl)-2-(2-hydroxyethyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide in place of N-(3-chloro-4-fluorophenyl)-2-(2-hydroxyethyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide and pyrrolidine in place of dimethylamine. C19H20BrN5O. 414.1, 416.1 (M+1).
    Figure imgb0613
  • N-(3-bromophenyl)-N'-hydroxy-2-(2-(pyrrolidin-1-yl)ethyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide. To a suspension of N-(3-bromophenyl)-2-(2-(pyrrolidin-1-yl)ethyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide (54 mg, 0.13 mmol) in 1,2-dichloroethane (1.0 mL) and phosphorus oxychloride (1.0 mL) was added phosphorus pentachloride (33 mg, 0.16 mmol). The mixture was stirred at 90 °C for 1 h. Another portion of phosphorus pentachloride (33 mg, 0.16 mmol) was then added, and stirring resumed for an additional 45 min at 90 °C. A third portion of phosphorus pentachloride (33 mg, 0.16 mmol) was then added, and stirring resumed for an additional 1h at 90 °C. The reaction mixture was then cooled to room temperature and concentrated under reduced pressure. The resulting residue was treated with hydroxylamine (50 wt. % in water, 1.0 mL, 16 mmol) in ethanol (1.0 mL) with vigorous stirring. The mixture was stirred for 15 min, then diluted with saturated aqueous sodium chloride and dichloromethane/isopropanol (2:1). The layers were then separated, and the organic phase was concentrated under reduced pressure. The resulting crude residue was suspended in 30% methanol in dichloromethane, filtered to remove salts, and loaded directly onto a silica gel cartridge for purification by flash chromatography (0-50% methanol/dichloromethane). Product-containing fractions were pooled and concentrated under reduced pressure, then taken up in 5% methanol in dichloromethane and filtered through celite to remove silica gel that may have eluted from the column with the material. The filtrate was concentrated under reduced pressure, coevaporated with methanol (3x) to remove residual dichloromethane, dissolved in methanol/water, frozen, and lyophilized to afford the product as an off-white solid (30 mg). C19H21BrN6O. 429.1, 431.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 11.07 (s, 1H), 8.90 (s, 1H), 8.27 (d, J = 5.1 Hz, 1H), 7.15 - 7.09 (m, 1H), 7.01 - 6.96 (m, 1H), 6.95 - 6.88 (m, 2H), 6.51 - 6.47 (m, 1H), 3.71 - 2.85 (m, 8H), 1.89 (s, 4H).
    • Example 270: N-(2-(7-(N-(3-chloro-4-fluorophenyl)-N'-hydroxycarbamimidoyl)-1H-imidazo[4,5-b]pyridin-2-yl)ethyl)acetamide
  • Figure imgb0614
  • A solution of 4-(3-chloro-4-fluorophenyl)-3-(2-(2-((2,4-dimethoxybenzyl)amino)ethyl)-1H-imidazo[4,5-b]pyridin-7-yl)-1,2,4-oxadiazol-5(4H)-one (15 mg, 0.029 mmol) and 4-(dimethylamino)pyridine (1 flake) in dichloromethane (1 mL) was treated with acetic anhydride (0.027 mL, 0.29 mmol) and stirred at room temperature for 10 min. The reaction mixture was then concentrated under reduced pressure. The resulting residue was dissolved in dichloromethane (0.5 mL) and treated with triethylsilane (0.022 mL, 0.14 mmol) followed by trifluoroacetic acid (0.5 mL). The reaction solution was stirred at room temperature overnight, then concentrated under reduced pressure, taken up in tetrahydrofuran (1 mL) and water (1 mL), and treated with a 2M aqueous solution of sodium hydroxide (1 mL, 2 mmol). After stirring for 15 min, the mixture was acidified with acetic acid, diluted with dimethyl sulfoxide, and purified by reverse phase preparative HPLC to provide the desired product (9 mg). C17H16ClFN6O2. 391.1 (M+1).
    • Example 271: N-(3-chlorophenyl)-N'-hydroxy-2-(2-(piperidin-1-yl)ethyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0615
  • N-(3-chlorophenyl)-2-(2-(piperidin-1-yl)ethyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide was made analogously to Example 184 using N-(3-chlorophenyl)-2-(2-hydroxyethyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide in place of N-(3-chloro-4-fluorophenyl)-2-(2-hydroxyethyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide and piperidine in place of dimethylamine. C20H22ClN5O. 384.3 (M+1).
    Figure imgb0616
  • N-(3-chlorophenyl)-N'-hydroxy-2-(2-(piperidin-1-yl)ethyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide was made analogously to Example 184 using N-(3-chlorophenyl)-2-(2-(piperidin-1-yl)ethyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide in place of N-(3-chloro-4-fluorophenyl)-2-(2-(dimethylamino)ethyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide. C20H23ClN6O. 399.2 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 8.91 (s, 1H), 8.27 (dd, J = 5.0, 0.7 Hz, 1H), 7.11 (d, J = 5.0 Hz, 1H), 6.98 (t, J = 8.0 Hz, 1H), 6.84 - 6.76 (m, 2H), 6.46 (dd, J = 8.2, 2.1 Hz, 1H), 3.67 - 2.70 (m, 8H), 1.73 (s, 4H), 1.53 (s, 2H).
    • Example 272: N-(3-bromophenyl)-N'-hydroxy-2-(2-(piperidin-1-yl)ethyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0617
  • N-(3-bromophenyl)-2-(2-(piperidin-1-yl)ethyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide was made analogously to Example 184 using N-(3-bromophenyl)-2-(2-hydroxyethyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide in place of N-(3-chloro-4-fluorophenyl)-2-(2-hydroxyethyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide and piperidine in place of dimethylamine. C20H22BrN5O. 428.3, 430.3 (M+1).
    Figure imgb0618
  • N-(3-bromophenyl)-N'-hydroxy-2-(2-(piperidin-1-yl)ethyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide was made analogously to Example 184 using N-(3-bromophenyl)-2-(2-(piperidin-1-yl)ethyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide in place of N-(3-chloro-4-fluorophenyl)-2-(2-(dimethylamino)ethyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide. C20H23BrN6O. 443.1, 445.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 11.07 (s, 1H), 8.90 (s, 1H), 8.27 (dd, J = 5.1, 0.8 Hz, 1H), 7.12 (d, J = 4.5 Hz, 1H), 6.98 - 6.96 (m, 1H), 6.95 - 6.89 (m, 2H), 6.52 - 6.47 (m, 1H), 3.63 - 2.72 (m, 8H), 1.88 - 1.35 (m, 6H).
    • Example 273: Methyl (2-(7-(N-(3-chloro-4-fluorophenyl)-N'-hydroxycarbamimidoyl)-1H-imidazo[4,5-b]pyridin-2-yl)ethyl)carbamate
  • Figure imgb0619
  • A solution of 4-(3-chloro-4-fluorophenyl)-3-(2-(2-((2,4-dimethoxybenzyl)amino)ethyl)-1H-imidazo[4,5-b]pyridin-7-yl)-1,2,4-oxadiazol-5(4H)-one (30 mg, 0.057 mmol) and N,N-diisopropylethylamine (0.20 mL, 1.2 mmol) in dichloromethane (1 mL) was treated with methyl chloroformate (0.044 mL, 0.57 mmol) dropwise and with stirring. After 1 h, another portion of methyl chloroformate (0.044 mL, 0.57 mmol) was added, and the reaction mixture was stirred for an additional 5 min. The mixture was the concentrated under reduced pressure. The resulting residue was dissolved in dichloromethane (0.5 mL) and treated with triethylsilane (0.046 mL, 0.29 mmol) followed by trifluoroacetic acid (0.5 mL). The reaction solution was stirred at room temperature overnight, then concentrated under reduced pressure, taken up in tetrahydrofuran (0.75 mL) and water (0.75 mL), and treated with a 2M aqueous solution of sodium hydroxide (1.5 mL, 3 mmol). After stirring for 5 min, the mixture was acidified with acetic acid, diluted with dimethyl sulfoxide, and purified by reverse phase preparative HPLC to provide the desired product. C17H16ClFN6O3. 407.1 (M+1).
    • Example 274: N-(3-chloro-4-fluorophenyl)-2-(2-((2,4-dimethoxybenzyl)amino)ethyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0620
  • 4-(3-chloro-4-fluorophenyl)-3-(2-(2-((2,4-dimethoxybenzyl)amino)ethyl)-1H-imidazo[4,5-b]pyridin-7-yl)-1,2,4-oxadiazol-5(4H)-one. A solution of 2-(7-(4-(3-chloro-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-1-(methylsulfonyl)-3H-imidazo[4,5-b]pyridin-2-yl)ethyl methanesulfonate (60 mg, 0.11 mmol) in acetonitrile (2.2 mL) was treated with 2,4-dimethoxybenzylamine (0.34 mL, 2.2 mmol). The resulting solution was stirred for 2.5 h at room temperature. The reaction mixture was then concentrated under reduced pressure, and the resulting residue was taken up in dichloromethane (1 mL) and treated with trifluoroacetic acid (1 mL). The solution was stirred overnight at room temperature, then concentrated under reduced pressure. The crude material was dissolved in dichloromethane and washed with saturated aqueous potassium carbonate. The aqueous layer was extracted twice with dichloromethane, and the combined organic layers were loaded onto a silica gel cartridge for purification by flash chromatography (0-20% methanol/dichloromethane) to provide the desired product. C25H22ClFN6O4. 525.2 (M+1).
    Figure imgb0621
  • N-(3-chloro-4-fluorophenyl)-2-(2-((2,4-dimethoxybenzyl)amino)ethyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide was made analogously to Example 177 using 4-(3-chloro-4-fluorophenyl)-3-(2-(2-((2,4-dimethoxybenzyl)amino)ethyl)-1H-imidazo[4,5-b]295yridine-7-yl)-1,2,4-oxadiazol-5(4H)-one in place of 4-(3-chloro-4-fluorophenyl)-3-(2-(hydroxymethyl)-1H-imidazo[4,5-b]295yridine-7-yl)-1,2,4-oxadiazol-5(4H)-one. C24H24ClFN6O3. 499.2 (M+1).
    • Example 275: 2-(2-(4-benzylpiperidin-1-yl)ethyl)-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0622
  • Example 275 was made analogously to Example 184 using 4-benzylpiperidine in place of dimethylamine. C27H28ClFN6O. 507.2 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 8.91 (s, 1H), 8.29 (d, J = 5.1 Hz, 1H), 7.34 - 7.25 (m, 2H), 7.24 - 7.12 (m, 4H), 7.03 (t, J = 9.1 Hz, 1H), 6.92 (dd, J = 6.4, 2.7 Hz, 1H), 6.55 - 6.46 (m, 1H), 3.51 (s, 4H), 3.29 (t, J = 7.4 Hz, 2H), 2.96 (s, 2H), 2.62 - 2.48 (m, 2H), 1.78 (d, J = 14.5 Hz, 3H), 1.41 (s, 2H).
    • Example 276: 2-(2-(3-azabicyclo[3.3.1]nonan-3-yl)ethyl)-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0623
  • Example 276 was made analogously to Example 184 using 3-azabicyclo[3.3.1]nonane hydrochloride and N,N-diisopropylethylamine in place of dimethylamine. C23H26ClFN6O. 457.2 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 11.07 (s, 1H), 8.93 (s, 1H), 8.32 (dd, J = 5.0, 3.2 Hz, 1H), 7.14 (dd, J = 5.0, 3.0 Hz, 1H), 7.05 (td, J = 9.1, 3.0 Hz, 1H), 6.93 - 6.88 (m, 1H), 6.50 (ddd, J = 8.7, 6.2, 2.6 Hz, 1H), 3.69 (d, J = 12.4 Hz, 2H), 3.54 - 3.47 (m, 2H), 3.41 - 3.34 (m, 2H), 3.25 (d, J = 12.3 Hz, 2H), 2.14 (s, 3H), 1.89 - 1.57 (m, 7H).
    • Example 277: 2-(2-(3-azabicyclo[3.2.1]octan-3-yl)ethyl)-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0624
  • Example 277 was made analogously to Example 184 using 3-azabicyclo[3.2.1]octane hydrochloride and N,N-diisopropylethylamine in place of dimethylamine. C22H24ClFN6O. 443.2 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 11.07 (s, 1H), 8.92 (s, 1H), 8.31 (d, J = 5.1 Hz, 1H), 7.15 (d, J = 5.1 Hz, 1H), 7.05 (t, J = 9.0 Hz, 1H), 6.92 (dd, J = 6.5, 2.6 Hz, 1H), 6.53 - 6.46 (m, 1H), 3.50 (t, J = 6.9 Hz, 2H), 3.42 (d, J = 11.7 Hz, 2H), 3.30 (t, J = 7.2 Hz, 2H), 3.08 (d, J = 11.6 Hz, 2H), 2.40 (s, 2H), 1.80 (s, 4H), 1.70 (d, J = 11.2 Hz, 1H), 1.49 (d, J = 10.0 Hz, 1H).
    • Example 278: N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((1-methylpiperidin-3-yl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0625
  • Example 278 was made analogously to Example 212 using 1-methylpiperidin-3-amine in place of 2-methoxyethanamine. C19H21ClFN7O. 418.2 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 11.36 (s, 1H), 9.79 (s, 1H), 8.95 (s, 1H), 7.98 (d, J = 5.1 Hz, 1H), 7.10 (t, J = 9.1 Hz, 1H), 7.05 - 6.90 (m, 2H), 6.61 - 6.55 (m, 1H), 4.18 - 4.01 (m, 1H), 2.97 - 2.72 (m, 6H), 2.11 - 1.62 (m, 4H), 1.57 - 1.41 (m, 1H).
    • Examples 279 and 280: (S)-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((2-(3-hydroxypyrrolidin-1-yl)ethyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide and (S)-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(3-hydroxypyrrolidin-1-yl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0626
  • A solution of 3-(2-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one (25 mg, 0.050 mmol) in DMSO (0.5 mL) was treated with (S)-1-(2-aminoethyl)pyrrolidin-3-ol (13 mg, 0.10 mmol). The solution was stirred at 60 °C overnight, then cooled to room temperature, diluted with ethyl acetate, and washed with saturated aqueous sodium chloride (3 x). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was dissolved in dichloromethane (0.5 mL) and treated with trifluoroacetic acid (0.5 mL). The solution was stirred at room temperature for 1 h, then concentrated under reduced pressure, taken up in tetrahydrofuran (0.5 mL) and water (0.5 mL) and treated with 2M aqueous sodium hydroxide (0.99 mL, 2.0 mmol). After stirring for 10 min, the mixture was acidified with acetic acid, diluted with dimethyl sulfoxide, and purified by reverse phase preparative HPLC to provide (S)-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((2-(3-hydroxypyrrolidin-1-yl)ethyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide (10 mg) and (S)-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(3-hydroxypyrrolidin-1-yl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide (4 mg).
    Figure imgb0627
  • (S)-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((2-(3-hydroxypyrrolidin-1-yl)ethyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide. C19H21ClFN7O2. 434.2 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 11.40 (s, 1H), 8.99 (s, 1H), 7.99 (d, J = 6.2 Hz, 1H), 7.15 - 7.07 (m, 1H), 7.04 - 6.98 (m, 1H), 6.98 - 6.93 (m, 1H), 6.61 - 6.54 (m, 1H), 4.45 (s, 1H), 4.16 - 2.91 (m, 8H), 2.14 (s, 1H), 1.94 - 1.82 (m, 1H).
    Figure imgb0628
  • (S)-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(3-hydroxypyrrolidin-1-yl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide. C17H16ClFN6O2. 391.1 (M+1). 1H NMR (400 MHz, DMSO-d 6) δ 11.38 (s, 1H), 9.03 (s, 1H), 8.02 - 7.94 (m, 1H), 7.11 - 7.03 (m, 2H), 6.91 (d, J = 6.0 Hz, 1H), 6.60 - 6.53 (m, 1H), 4.46 (s, 1H), 3.79 - 3.50 (m, 4H), 2.14 - 2.02 (m, 1H), 1.98 (s, 1H).
    • Example 281: N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((1-(2-methoxyethyl)pyrrolidin-3-yl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0629
  • Example 281 was made analogously to Example 212 using 1-(2-methoxyethyl)pyrrolidin-3-amine in place of 2-methoxyethanamine. C20H23ClFN7O2. 448.2 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 11.32 (s, 1H), 9.98 (s, 1H), 8.95 (s, 1H), 7.99 (d, J = 4.3 Hz, 1H), 7.09 (t, J = 9.1 Hz, 1H), 7.04 - 6.92 (d, J = 17.3 Hz, 3H), 6.57 (ddd, J = 8.3, 5.8, 2.4 Hz, 1H), 4.70 - 4.49 (m, 2H), 4.00 - 3.09 (m, 10H), 2.08 (s, 1H), 1.97 (s, 1H).
    • Example 282: N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(((4-methylmorpholin-3-yl)methyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0630
  • Example 282 was made analogously to Example 212 using (4-methylmorpholin-3-yl)methanamine in place of 2-methoxyethanamine. C19H21ClFN7O2. 434.2 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 11.40 (s, 1H), 8.97 (s, 1H), 7.99 (d, J = 6.3 Hz, 1H), 7.10 (t, J = 9.0 Hz, 1H), 7.01 (dd, J = 6.6, 2.6 Hz, 1H), 6.96 (d, J = 6.2 Hz, 1H), 6.57 (ddd, J = 9.0, 4.0, 2.7 Hz, 1H), 4.12 - 3.75 (m, 6H), 3.28 - 3.14 (m, 3H), 3.01 (s, 3H).
    • Example 283: N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((2-(pyrrolidin-1-yl)ethyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0631
  • Example 283 was made analogously to Example 212 using 2-(pyrrolidin-1-yl)ethan-1-amine in place of 2-methoxyethanamine. C19H21ClFN7O. 418.2 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 11.35 (s, 1H), 8.97 (s, 1H), 7.98 (d, J = 6.2 Hz, 1H), 7.10 (t, J = 9.0 Hz, 1H), 7.03 - 6.98 (m, 1H), 6.94 (d, J = 6.1 Hz, 1H), 6.57 (ddd, J = 9.1, 4.1, 2.8 Hz, 1H), 3.82 - 3.35 (m, 8H), 1.94 (s, 4H).
    • Example 284: N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(((4-((methylsulfonyl)methyl)tetrahydro-2H-pyran-4-yl)methyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0632
  • Example 284 was prepared analogously to Example 333 using 3-(2-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one, 2H-pyran-4-methanamine, tetrahydro-4-[(methylsulfonyl)methyl]- hydrochloride, and N,N-diisopropylethylamine in place of 3-(2-chloro-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one and tert-butyl (2-aminoethyl)carbamate (bis-TFA salt, white solid). C21H24ClFN6O4S. 511.4 (M+1). 1H NMR (400 MHz, DMSO-d6 ) δ 11.45 (s, 1H), 8.96 (s, 1H), 7.95 (d, J = 6.4 Hz, 1H), 7.12 (t, J = 9.0 Hz, 1H), 7.04 (dd, J = 6.5, 2.7 Hz, 1H), 6.92 (d, J = 6.4 Hz, 1H), 6.60 (ddd, J = 8.9, 4.0, 2.8 Hz, 1H), 3.85 (d, J = 6.6 Hz, 4H), 3.81 - 3.45 (m, 4H), 3.10 (s, 3H), 1.77 - 1.65 (m, 2H), 1.61 (dd, J = 8.5, 4.6 Hz, 2H). 19F NMR (377 MHz, DMSO-d6 ) δ -74.67 (6F), -126.62 (1F).
    • Example 285: N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((2-(methylsulfonyl)benzyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0633
  • Example 285 was prepared analogously to Example 333 using 3-(2-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one, (2-methylsulfonylphenyl)methanamine hydrochloride, and N,N-diisopropylethylamine in place of 3-(2-chloro-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one and tert-butyl (2-aminoethyl)carbamate (bis-TFA salt, white solid). C21H18ClFN6O3S. 489.4 (M+1). 1H NMR (400 MHz, DMSO-d6 ) δ 11.88 (br s, 1H), 11.43 (s, 1H), 8.95 (s, 1H), 8.31 (br s, 1H), 8.03 - 7.91 (m, 2H), 7.75 - 7.67 (m, 1H), 7.66 - 7.56 (m, 2H), 7.09 (t, J = 9.0 Hz, 1H), 7.03 (d, J = 6.3 Hz, 1H), 6.93 (d, J = 6.3 Hz, 1H), 6.59 (dt, J = 8.9, 3.5 Hz, 1H), 5.06 (d, J = 6.2 Hz, 2H), 3.39 (s, 3H). 19F NMR (376 MHz, DMSO-d6 ) δ -74.4 (6F), -126.6 (1F).
    • Example 286: 2-((1-acetylpiperidin-3-yl)amino)-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0634
  • Example 286 was prepared analogously to Example 333 using 3-(2-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one and 1-(3-aminopiperidin-1-yl)ethanone in place of 3-(2-chloro-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one and tert-butyl (2-aminoethyl)carbamate, respectively (bis-TFA salt, off-white solid). C20H21ClFN7O2. 446.4 (M+1). 1H NMR (400 MHz, DMSO-d6 ) δ 11.46 (s, 1H), 8.98 (s, 1H), 8.17 (br s, 1H), 7.98 (t, J = 6.6 Hz, 1H), 7.11 (td, J = 9.0, 4.1 Hz, 1H), 7.04 (td, J = 6.7, 2.6 Hz, 1H), 6.92 (dd, J = 8.6, 6.3 Hz, 1H), 6.66 - 6.51 (m, 1H), 4.06 - 3.70 (m, 3H), 3.30 - 3.20 (m, 3H), 2.01 (d, J = 27.2 Hz, 3H), 1.98 - 1.95 (m, 1H) 1.80 - 1.60 (m, 2H), 1.59 - 1.41 (m, 1H). 19F NMR (376 MHz, DMSO-d6 ) δ -74.53 (6F), -126.59 (1F).
    • Example 287: N-(3-chloro-4-fluorophenyl)-2-((ethylamino)methyl)-4-fluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0635
  • Methyl 4-fluoro-2-(methoxymethyl)-1H-benzo[d]imidazole-7-carboxylate was prepared analogously to Example 45, using methyl 2,3-diamino-4-fluorobenzoate in place of methyl 2,3-diamino-4,5-difluorobenzoate. C11H11FN2O3. 239.0 (M+1).
    Figure imgb0636
  • N-(3-chloro-4-fluorophenyl)-4-fluoro-2-(methoxymethyl)-1H-benzo[d]imidazole-7-carboxamide was prepared analogously to Example 45, using methyl 4-fluoro-2-(methoxymethyl)-1H-benzo[d]imidazole-7-carboxylate in place of methyl 4,5-difluoro-2-(methoxymethyl)-1H-benzo[d]imidazole-7-carboxylate. C16H12ClF2N3O2. 352.0 (M+1).
    Figure imgb0637
  • 4-(3-chloro-4-fluorophenyl)-3-(4-fluoro-2-(methoxymethyl)-1H-benzo[d]imidazol-7-yl)-1,2,4-oxadiazol-5(4H)-one was prepared analogously to Example 45, using N-(3-chloro-4-fluorophenyl)-4-fluoro-2-(methoxymethyl)-1H-benzo[d]imidazole-7-carboxamide in place of N-(3-chloro-4-fluorophenyl)-4,5-difluoro-2-(methoxymethyl)-1H-benzo[d]imidazole-7-carboxamide. C17H11ClF2N4O3. 393.0 (M+1).
    Figure imgb0638
  • 3-(2-(bromomethyl)-4-fluoro-1H-benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one was prepared analogously to Example 45, using 4-(3-chloro-4-fluorophenyl)-3-(4-fluoro-2-(methoxymethyl)-1H-benzo[d]imidazol-7-yl)-1,2,4-oxadiazol-5(4H)-one in place of 4-(3-chloro-4-fluorophenyl)-3-(4,5-difluoro-2-(methoxymethyl)-1H-benzo[d]imidazol-7-yl)-1,2,4-oxadiazol-5(4H)-one. C16H8BrClF2N4O2. 440.9/442.9 (M+1).
    Figure imgb0639
  • N-(3-chloro-4-fluorophenyl)-2-((ethylamino)methyl)-4-fluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide. Example 287 was prepared analogously to Example 45 using 3-(2-(bromomethyl)-4-fluoro-1H-benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one and ethylamine (2 M in THF) in place of 3-(2-(bromomethyl)-4,5-difluoro-1H-benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one and 3-methoxypropylamine, respectively. C17H16ClF2N5O. 360.1 (M+1).
    • Example 288: N-(3-chloro-4-fluorophenyl)-2-((dimethylamino)methyl)-4-fluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0640
  • Example 288 was prepared analogously to Example 45 using 3-(2-(bromomethyl)-4-fluoro-1H-benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one and dimethylamine (2 M in THF) in place of 3-(2-(bromomethyl)-4,5-difluoro-1H-benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one and 3-methoxypropylamine, respectively. C17H16ClF2N5O. 380.0 (M+1).
    • Example 289: N-(3-chloro-4-fluorophenyl)-4-fluoro-N'-hydroxy-2-((isopropylamino)methyl)-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0641
  • Example 289 was prepared analogously to Example 45 using 3-(2-(bromomethyl)-4-fluoro-1H-benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one and isopropylamine in place of 3-(2-(bromomethyl)-4,5-difluoro-1H-benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one and 3-methoxypropylamine, respectively. C18H18ClF2N5O. 394.1 (M+1).
    • Example 290: N-(3-chloro-4-fluorophenyl)-4-fluoro-N'-hydroxy-2-((methylamino)methyl)-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0642
  • Example 290 was prepared analogously to Example 45 using 3-(2-(bromomethyl)-4-fluoro-1H-benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one and methylamine (2 M in THF) in place of 3-(2-(bromomethyl)-4,5-difluoro-1H-benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one and 3-methoxypropylamine, respectively. C16H14ClF2N5O. 366.0 (M+1).
    • Example 291: 2-(aminomethyl)-N-(3-chloro-4-fluorophenyl)-4-fluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0643
  • Example 291 was prepared analogously to Example 45 using 3-(2-(bromomethyl)-4-fluoro-1H-benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one and ammonia (0.5 M in dioxane) in place of 3-(2-(bromomethyl)-4,5-difluoro-1H-benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one and 3-methoxypropylamine, respectively. C15H12ClF2N5O. 352.0 (M+1).
    • Example 292: N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((2-hydroxy-2-methylpropyl)amino)-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0644
  • Example 292 was prepared analogously to Example 333 using 1-amino-2-methylpropan-2-ol in place of tert-butyl (2-aminoethyl)carbamate. C18H17ClF3N5O2. 428.1 (M+1).
    • Example 293: N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((2-hydroxypropyl)amino)-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0645
  • Example 293 was prepared analogously to Example 333 using 1-aminopropan-2-ol in place of tert-butyl (2-aminoethyl)carbamate. C17H15ClF3N5O2. 414.1 (M+1).
    • Example 294: 2-((7-(N-(3-chloro-4-fluorophenyl)-N'-hydroxycarbamimidoyl)-4,5-difluoro-1H-benzo[d]imidazol-2-yl)amino)acetamide
  • Figure imgb0646
  • Example 294 was prepared analogously to Example 333 using 2-aminoacetamide in place of tert-butyl (2-aminoethyl)carbamate. C16H12ClF3N6O2. 413.3 (M+1).
    • Example 295: N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((2-hydroxyethyl)amino)-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0647
  • Example 295 was prepared analogously to Example 333 using 2-aminoethan-1-ol in place of tert-butyl (2-aminoethyl)carbamate. C16H13ClF3N5O2. 400.1 (M+1).
    • Example 296: N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((3-hydroxycyclobutyl)amino)-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0648
  • Example 296 was prepared analogously to Example 333 using 3-aminocyclobutanol in place of tert-butyl (2-aminoethyl)carbamate. C18H15ClF3N5O2. 426.3 (M+1).
    • Example 297: N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((3-(pyridin-2-ylamino)propyl)amino)-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0649
  • Example 297 was prepared analogously to Example 333 using N-(3-aminopropyl)pyridine-2-amine in place of tert-butyl (2-aminoethyl)carbamate. C22H19ClF3N7O. 490.3 (M+1).
    • Example 298: N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((2-sulfamoylethyl)amino)-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0650
  • Example 298 was prepared analogously to Example 333 using 2-aminoethanesulfonamide in place of tert-butyl (2-aminoethyl)carbamate. C16H14ClF3N6O3S. 463.1 (M+1).
    • Example 299: N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-(((1-methyl-1H-pyrazol-5-yl)methyl)amino)-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0651
  • Example 299 was prepared analogously to Example 333 using (1-methyl-1H-pyrazol-5-yl)methanamine in place of tert-butyl (2-aminoethyl)carbamate. C19H15ClF3N7O. 450.1 (M+1).
    • Example 300: 2-((2-(1H-pyrazol-1-yl)ethyl)amino)-N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0652
  • Example 300 was prepared analogously to Example 333 using 2-(1H-pyrazol-1-yl)ethan-1-amine in place of tert-butyl (2-aminoethyl)carbamate. C19H15ClF3N7O. 450.1 (M+1).
    • Example 301: 2-((7-(N-(3-chloro-4-fluorophenyl)-N'-hydroxycarbamimidoyl)-4,5-difluoro-1H-benzo[d]imidazol-2-yl)amino)-N,N-dimethylacetamide
  • Figure imgb0653
  • Example 301 was prepared analogously to Example 333 using glycine dimethylamide in place of tert-butyl (2-aminoethyl)carbamate. C18H16ClF3N6O2. 441.1 (M+1).
    • Example 302: N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-(2-hydroxy-2-methylpropyl)-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0654
  • 4,5-difluoro-2-(2-hydroxy-2-methylpropyl)-1H-benzo[d]imidazole-7-carboxylic acid. A mixture of 3-hydroxy-3-methylbutyric acid (1.6 mL, 15.1 mmol) and methyl 2,3-diamino-4,5-difluorobenzoate (1.529 g, 7.56 mmol) in HCl (7.5 mL of a 6 M aqueous soln) stirred at 120 °C in a sealed tube for 16 h. The mixture was cooled to rt and concentrated to remove HCl. The remaining solution was frozen and lyophilized to give the crude desired product. C12H12F2N2O3. 271.1 (M+1).
    Figure imgb0655
  • N-(3-chloro-4-fluorophenyl)-4,5-difluoro-2-(2-hydroxy-2-methylpropyl)-1H-benzo[d]imidazole-7-carboxamide was prepared analogously to Example 80 using 4,5-difluoro-2-(2-hydroxy-2-methylpropyl)-1H-benzo[d]imidazole-7-carboxylic acid and 3-chloro-4-fluoroaniline in place of 1Himidazo[4,5-b]pyridine-7-carboxylic acid and 3-bromoaniline, respectively. C18H15ClF3N3O2. 420.1 (M+23).
    Figure imgb0656
  • 2-(2-((tert-butyldimethylsilyl)oxy)-2-methylpropyl)-N-(3-chloro-4-fluorophenyl)-4,5-difluoro-1H-benzo[d]imidazole-7-carboxamide. To a solution of N-(3-chloro-4-fluorophenyl)-4,5-difluoro-2-(2-hydroxy-2-methylpropyl)-1H-benzo[d]imidazole-7-carboxamide (0.145 g, 0.365 mmol) and 2,6-lutidine (0.34 mL, 2.9 mmol) in DCM (7 mL) at 0 °C was added tert-butyldimethylsilyl trifluoromethanesulfonate (0.17 mL, 0.740 mmol). The mixture warmed to rt and stirred 48 h. 2,6-Lutidine (0.34 mL, 2.9 mmol) and tert-butyldimethylsilyl trifluoromethanesulfonate (0.34 mL, 1.48 mmol) were added. After 4 h, 2,6-lutidine (0.34 mL, 2.9 mmol) and tert-butyldimethylsilyl trifluoromethanesulfonate (0.34 mL, 1.48 mmol) were added and the mixture stirred 4 h. The mixture was concentrated onto silica gel and purified via silica gel chromatography to give the desired product. C24H29ClF3N3O2Si. 512.2 (M+1).
    Figure imgb0657
  • 2-(2-((tert-butyldimethylsilyl)oxy)-2-methylpropyl)-N-(3-chloro-4-fluorophenyl)-4,5-difluoro-1H-benzo[d]imidazole-7-carbothioamide was prepared analogously to Example 13, using 2-(2-((tert-butyldimethylsilyl)oxy)-2-methylpropyl)-N-(3-chloro-4-fluorophenyl)-4,5-difluoro-1H-benzo[d]imidazole-7-carboxamide in place of 2-amino-N-(3-chloro-4-fluorophenyl)-4,5-difluoro-1H-benzo[d]imidazole-7-carboxamide. C24H29ClF3N3OSSi. 528.3 (M+1).
    Figure imgb0658
  • 2-(2-((tert-butyldimethylsilyl)oxy)-2-methylpropyl)-N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide was prepared analogously to Example 13, using 2-(2-((tert-butyldimethylsilyl)oxy)-2-methylpropyl)-N-(3-chloro-4-fluorophenyl)-4,5-difluoro-1H-benzo[d]imidazole-7-carbothioamide in place of 2-amino-N-(3-chloro-4-fluorophenyl)-4,5-difluoro-1H-benzo[d]imidazole-7-carbothioamide. C24H30ClF3N4O2Si. 527.3 (M+1).
    Figure imgb0659
  • N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-(2-hydroxy-2-methylpropyl)-1H-benzo[d]imidazole-7-carboximidamide. To a soln of 2-(2-((tert-butyldimethylsilyl)oxy)-2-methylpropyl)-N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide (0.007 g, 0.013 mmol) in THF (1 mL) at 0 °C was added HF·pyridine (0.02 mL, 0.664 mmol). Mixture warmed to rt and stirred 16 h. HF·pyridine (0.04 mL, 1.32 mmol) was added and mixture stirred an additional 24 h. The mixture was diluted with EtOAc and washed with sat NaHCO3 soln. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine and concentrated. The residue was purified by silica gel chromatography to give the desired product (0.001 g). C18H16ClF3N4O2. 413.1 (M+H).
    • Example 303: N-(3-chloro-4-fluorophenyl)-2-((4-(dimethylamino)butyl)amino)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0660
  • Example 303 was prepared analogously to Example 333 using 4-dimethylaminobutan-1-amine in place of tert-butyl (2-aminoethyl)carbamate. C20H22ClF3N6O. 455.2 (M+H).
    • Example 304: N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((piperidin-3-ylmethyl)amino)-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0661
  • Example 304 was prepared analogously to Example 333 using 1-Boc-3-(aminomethyl)piperidine in place of tert-butyl (2-aminoethyl)carbamate. C20H20ClF3N6O. 453.2 (M+H).
    • Example 305: N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((1-methylpiperidin-2-yl)methyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0662
  • 2-((1-methylpiperidin-2-yl)methyl)-1H-imidazo[4,5-b]pyridine-7-carboxylic acid. A suspension of 2,3-diaminoisonicotinic acid hydrochloride (200 mg, 0.106 mmol) and 2-(1-methylpiperidin-2-yl)acetic acid (498 mg, 0.317 mmol) in sulfuric acid (1.5 mL) was stirred at room temperature for 5 min and, then, was sealed in a vial and stirred at 160 °C for 3 hours. Once the mixture had cooled, water (2 mL) was added and the solution was purified by preparative HPLC to give the desired product. C14H18N4O2. 275.1 (M+1).
    Figure imgb0663
  • N-(3-chloro-4-fluorophenyl)-2-((1-methylpiperidin-2-yl)methyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide. A solution of 2-((1-methylpiperidin-2-yl)methyl)-1H-imidazo[4,5-b]pyridine-7-carboxylic acid (75 mg, 0.273 mmol), 4-fluoro-3-chloroaniline (60 mg, 0.410 mmol), bis(2-oxo-3-oxazolidinyl)phosphinic chloride (139 mg, 0.547 mmol) and N,N-diisopropylethylamine (0.240 ml, 1.37 mmol) in dichloromethane (1.5 mL) was stirred for 3 hours. The reaction mixture was concentrated and purified by preparative HPLC. The resulting lyophilized material was mixed with saturated aqueous sodium bicarbonate (5 mL), filtered, washed with water and dried on high vacuum to give the desired product. C20H21ClFN5O. 402.1 (M+1).
    Figure imgb0664
  • N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((1-methylpiperidin-2-yl)methyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide. To a mixture ofN-(3-chloro-4-fluorophenyl)-2-((1-methylpiperidin-2-yl)methyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide (11 mg, 0.027 mmol) and potassium carbonate (26 mg, 0.192 mmol) in dichloromethane (0.5 ml) was added phosphorous pentachloride (11 mg, 0.055 mmol). The reaction mixture stirred for 2 hours and was concentrated. The residue was brought up in ethanol (0.5 ml) and hydroxylamine (0.07 mL, 50% in water, 1.08 mmol) and stirred for 1 hour. The reaction mixture was concentrated and purified by preparative HPLC to give the desired product. C20H22ClFN6O. 417.1 (M+1).
    • Example 306: N-(3-bromophenyl)-N'-hydroxy-2-((2-morpholinoethyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0665
  • Example 306 was prepared analogously to Example 333 using 4-(3-bromophenyl)-3-(2-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-7-yl)-1,2,4-oxadiazol-5(4H)-one and 2-morpholinoethan-1-amine in place of 3-(2-chloro-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one and tert-butyl (2-aminoethyl)carbamate, respectively. C19H22BrN7O2. 460.2/462.1 (M+H). 1H NMR (400 MHz, DMSO-d6) δ 11.35 (s, 1H), 8.94 (s, 1H), 7.98 (d, J = 6.1 Hz, 1H), 7.09 - 6.95 (m, 3H), 6.93 (d, J = 5.9 Hz, 1H), 6.61 - 6.50 (m, 1H), 3.95 - 3.20 (m, 12H).
    • Example 307: N-(3-chloro-4-fluorophenyl)-5-fluoro-N'-hydroxy-4-methoxy-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0666
  • N-(3-chloro-4-fluorophenyl)-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-7-carboxamide. To a solution of N-(3-chloro-4-fluorophenyl)-4,5-difluoro-1H-benzo[d]imidazole-7-carboxamide (1.92 g, 5.89 mmol) and TEA (3.3 mL, 23.6 mmol) in DCM (60 mL) was added SEMCl (2.6 mL, 14.7 mmol). After 45 min, TEA (1.1 mL, 7.9 mmol) and SEMCl (0.9 mL, 4.9 mmol) were added. After 20 min, the mixture was diluted with EtOAc, concentrated onto silica gel, and purified via silica gel chromatography to give the desired product. C20H21ClF3N3O2Si. 456.2 (M+1).
    Figure imgb0667
  • N-(3-chloro-4-fluorophenyl)-5-fluoro-4-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-7-carboxamide. A mixture of N-(3-chloro-4-fluorophenyl)-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-7-carboxamide (0.250 g, 0.548 mmol) and sodium methoxide (0.50 mL of a 25% soln in MeOH, 2.19 mmol) in MeOH (1 mL) was stirred at 65 °C for 8 h. Mixture was cooled to rt and diluted with sat. NH4Cl soln. The aqueous layer was extracted 3 × with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated to give the desired product. C21H24ClF2N3O3Si. 468.3 (M+1).
    Figure imgb0668
  • N-(3-chloro-4-fluorophenyl)-5-fluoro-N'-hydroxy-4-methoxy-1H-benzo[d]imidazole-7-carboximidamide was prepared analogously to Example 305 using N-(3-chloro-4-fluorophenyl)-5-fluoro-4-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-7-carboxamide in place of N-(3-chloro-4-fluorophenyl)-2-((1-methylpiperidin-2-yl)methyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide. C15H11ClF2N4O2. 353.1 (M+H).
    • Example 308: N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((pyridin-2-ylmethyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0669
  • Example 308 was prepared analogously to Example 333 using 3-(2-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one and 2-picolylamine in place of 3-(2-chloro-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one and tert-butyl (2-aminoethyl)carbamate, respectively. C19H15ClFN7O. 412.2 (M+H). 1H NMR (400 MHz, DMSO-d6) δ 11.48 (s, 1H), 8.99 (s, 1H), 8.59 (ddd, J = 4.9, 1.8, 0.9 Hz, 1H), 7.98 (d, J = 6.4 Hz, 1H), 7.84 (td, J = 7.7, 1.8 Hz, 1H), 7.42 (d, J = 7.9 Hz, 1H), 7.36 (ddd, J = 7.4, 5.0, 1.1 Hz, 1H), 7.11 (t, J = 9.0 Hz, 1H), 7.05 (dd, J = 6.5, 2.7 Hz, 1H), 6.95 (d, J = 6.3 Hz, 1H), 6.60 (ddd, J = 9.0, 3.9, 3.0 Hz, 1H), 4.80 (d, J = 5.7 Hz, 2H).
    • Example 309: 2-((2-(1H-pyrazol-1-yl)ethyl)amino)-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0670
  • Example 309 was prepared analogously to Example 333 using 3-(2-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one and 2-(1H-pyrazol-1-yl)ethan-1-amine in place of 3-(2-chloro-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one and tert-butyl (2-aminoethyl)carbamate, respectively. C18H16ClFN8O. 415.2 (M+H).
    • Example 310: N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(((1-methyl-1H-pyrazol-3-yl)methyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0671
  • Example 310 was prepared analogously to Example 333 using 3-(2-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one and (1-methyl-1H-pyrazol-3-yl)methanamine in place of 3-(2-chloro-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one and tert-butyl (2-aminoethyl)carbamate, respectively. C18H16ClFN8O. 415.2 (M+H).
    • Example 311: N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((4,4,4-trifluorobutyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0672
  • Example 311 was prepared analogously to Example 333 using 3-(2-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one and 4,4,4-trifluorobutylamine in place of 3-(2-chloro-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one and tert-butyl (2-aminoethyl)carbamate, respectively. C17H15ClF4N6O. 431.1 (M+H).
    • Example 312: N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((3,3,3-trifluoropropyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0673
  • Example 312 was prepared analogously to Example 333 using 3-(2-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one and 3,3,3-trifluoropropylamine in place of 3-(2-chloro-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one and tert-butyl (2-aminoethyl)carbamate, respectively. C16H13ClF4N6O. 417.1 (M+H). 1H NMR (400 MHz, DMSO-d6) δ 11.42 (s, 1H), 8.98 (s, 1H), 7.97 (d, J = 6.2 Hz, 1H), 7.10 (t, J = 9.0 Hz, 1H), 7.03 (dd, J = 6.3, 2.4 Hz, 1H), 6.94 (d, J = 6.3 Hz, 1H), 6.58 (ddd, J = 9.0, 4.0, 3.0 Hz, 1H), 3.78 - 3.63 (m, 2H), 2.76 - 2.56 (m, 2H).
    • Example 313: N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((2-(2-methoxyethoxy)ethyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0674
  • Example 313 was prepared analogously to Example 333 using 3-(2-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one and 2-(2-methoxyethoxy)ethanamine in place of 3-(2-chloro-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one and tert-butyl (2-aminoethyl)carbamate, respectively. C18H20ClN6O3. 423.2 (M+H).
    • Example 314: N-(3-chloro-4-fluorophenyl)-2-((3-(cyclopropyl(methyl)amino)propyl)amino)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0675
  • 2-(3-(cyclopropyl(methyl)amino)propyl)isoindoline-1,3-dione. A solution of 2-(3-bromopropyl)isoindoline-1,3-dione (1.89 g, 7.03 mmol), cyclopropylmethylamine (0.59 mL, 7.03 mmol), and potassium carbonate (1.94 g, 14 mmol) in dimethylformamide (7 mL) was stirred at 40 °C for 6 hr. Water was added and the aqueous layer was washed three times with diethyl ether. The combined organic layers were washed with brine and dried over magnesium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography to give the desired product (1.8 g). C15H18N2O2. 259.2 (M+1).
    Figure imgb0676
  • N-(3-chloro-4-fluorophenyl)-2-((3-(cyclopropyl(methyl)amino)propyl)amino)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide. A solution of 2-(3-(cyclopropyl(methyl)amino)propyl)isoindoline-1,3-dione (63 mg, 0.24 mmol) and hydrazine (0.006 mL, 0.2 mmol) in ethanol (1 mL) was stirred at 80 °C for one hour. The reaction was cooled to room temperature, filtered and concentrated. To the resulting residue was added 3-(2-chloro-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one (24 mg, 0.024 mmol), and dimethylsulfoxide (0.25 mL). The resulting solution was stirred at 65 °C for one hour. The reaction mixture was cooled and diluted with ethyl acetate and washed three times with saturated aqueous sodium chloride. The organic layer was dried over sodium sulfate, filtered and concentrated. The resulting residue was brought up in dichloromethane (0.5 mL) and trifluoroacetic acid (0.5 mL) and stirred for 3 hours. The reaction solution was concentrated. The resulting residue was brought up in tetrahydrofuran (0.2 mL) and methanol (0.2 mL) and to this solution was added 2 N sodium hydroxide (0.24 mL, 0.48 mmol). The resulting solution was stirred for 30 min and concentrated and purified by preparative HPLC to give the desired product (9 mg). C20H23ClFN7O. 432.2 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 11.34 (s, 1H), 8.95 (s, 1H), 7.96 (d, J = 6.2 Hz, 1H), 7.09 (t, J = 9.0 Hz, 1H), 7.00 (d, J = 5.6 Hz, 1H), 6.92 (d, J = 6.1 Hz, 1H), 6.61 - 6.53 (m, 1H), 3.54 - 3.42 (m, 2H), 3.30 - 3.19 (m, 3H), 2.92 - 2.77 (m, 5H), 2.05 - 1.92 (m, 3H), 0.96 - 0.78 (m, 6H).
    • Example 315: N-(3-chloro-4-fluorophenyl)-2-((3-(cyclopropylamino)propyl)amino)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0677
  • 2-(3-(cyclopropylamino)propyl)isoindoline-1,3-dione was prepared analogously to Example 314 using cyclopropylamine in place of cyclopropylmethylamine. C14H16N2O2. 245.1 (M+1).
    Figure imgb0678
  • N-(3-chloro-4-fluorophenyl)-2-((3-(cyclopropylamino)propyl)amino)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide was prepared analogously to Example 314 using 2-(3-(cyclopropylamino)propyl)isoindoline-1,3-dione in place of 2-(3-(cyclopropyl(methyl)amino)propyl)isoindoline-1,3-dione. C19H21ClFN7O. 418.2 (M+H).
    • Example 316: N-(3-chloro-4-fluorophenyl)-2-((3-(cyclopropyl(ethyl)amino)propyl)amino)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0679
  • 2-(3-(cyclopropyl(ethyl)amino)propyl)isoindoline-1,3-dione was prepared analogously to Example 314 using N-ethylcyclopropylamine in place of cyclopropylmethylamine. C16H20N2O2. 273.2 (M+1).
    Figure imgb0680
  • N-(3-chloro-4-fluorophenyl)-2-((3-(cyclopropyl(ethyl)amino)propyl)amino)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide was prepared analogously to Example 314 using 2-(3-(cyclopropyl(ethyl)amino)propyl)isoindoline-1,3-dione in place of 2-(3-(cyclopropyl(methyl)amino)propyl)isoindoline-1,3-dione. C21H25ClFN7O. 446.2 (M+H). 1H NMR (400 MHz, DMSO-d6) δ 11.33 (s, 1H), 8.96 (s, 1H), 7.97 (d, J = 6.1 Hz, 1H), 7.10 (t, J = 9.0 Hz, 1H), 7.05 - 6.98 (m, 1H), 6.97 - 6.89 (m, 1H), 6.58 (dt, J = 8.9, 3.5 Hz, 1H), 3.51 (s, 2H), 3.35 - 3.18 (m, 4H), 2.94 - 2.73 (m, 1H), 2.15 - 1.92 (m, 2H), 1.26 (t, J = 7.3 Hz, 3H), 1.02 - 0.78 (m, 4H).
    • Example 317: N-(3-chloro-4-fluorophenyl)-2-((2-(4-fluoropiperidin-1-yl)ethyl)amino)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0681
  • Example 317 was prepared analogously to Example 333 using 3-(2-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one and 2-(4-fluoropiperidin-1-yl)ethan-1-amine in place of 3-(2-chloro-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one and tert-butyl (2-aminoethyl)carbamate, respectively. C20H22ClF2N7O. 450.2 (M+H). 1H NMR (400 MHz, DMSO-d6) δ 11.30 (s, 1H), 8.94 (s, 1H), 7.98 (d, J = 5.6 Hz, 1H), 7.10 (t, J = 9.1 Hz, 1H), 6.99 (d, J = 5.7 Hz, 1H), 6.96 - 6.85 (m, 1H), 6.64 - 6.45 (m, 1H), 5.10-4.80 (m, 1H), 3.86 - 3.70 (m, 2H), 3.50 - 3.20 (m, 6H), 2.23 - 1.93 (m, 4H).
    • Example 318: N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((2-(2,2,2-trifluoroethoxy)ethyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0682
  • Example 318 was prepared analogously to Example 229 using 3-(2-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one and 2-(2,2,2-trifluoroethoxy)ethan-1-amine hydrochloride in place of 3-(2-chloro-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one and 3-aminopropanamide hydrochloride, respectively. C17H15ClF4N6O2. 447.1 (M+H).
    • Example 319: N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((3-(2,2,2-trifluoroethoxy)propyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0683
  • Example 319 was prepared analogously to Example 229 using 3-(2-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one and 3-(2,2,2-trifluoroethoxy)propan-1-amine hydrochloride in place of 3-(2-chloro-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one and 3-aminopropanamide hydrochloride, respectively. C18H17ClF4N6O2. 461.2 (M+H). 1H NMR (400 MHz, DMSO-d6) δ 11.36 (s, 1H), 8.94 (s, 1H), 7.94 (d, J = 6.2 Hz, 1H), 7.08 (t, J = 9.0 Hz, 1H), 7.01 (dd, J = 6.5, 2.3 Hz, 1H), 6.89 (d, J = 6.3 Hz, 1H), 6.56 (ddd, J = 8.9, 3.9, 2.8 Hz, 2H), 4.04 (q, J = 9.5 Hz, 2H), 3.65 (t, J = 6.1 Hz, 2H), 3.52 - 3.42 (m, 2H), 1.85 (p, J = 6.9 Hz, 2H).
    • Example 320: N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((2-(3-methoxypiperidin-1-yl)ethyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0684
  • tert-Butyl (2-(3-methoxypiperidin-1-yl)ethyl)carbamate. A mixture of tert-butyl (2-bromoethyl)carbamate (0.147 g, 0.656 mmol), 3-methoxypiperidine hydrochloride (0.099 g, 0.656 mmol) and DIPEA (0.25 mL, 1.44 mmol) in DMSO (1.5 mL) was stirred at 40 °C for 16 h. The mixture was diluted with sat NaHCO3 soln. The aqueous layer was extracted 3 × with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated. The residue was purified via silica gel chromatography to give the desired product (0.047 g). C13H26N2O3. 259.2 (M+1).
    Figure imgb0685
  • 2-(3-Methoxypiperidin-1-yl)ethan-1-amine. To a solution of tert-butyl (2-(3-methoxypiperidin-1-yl)ethyl)carbamate (0.047 g, 0.182 mmol) in THF was added HCl (2.3 mL of a 4 M soln in dioxane, 9.1 mmol). The mixture stirred at rt for 16 h. The mixture was concentrated to give the desired product as the HCl salt (0.042 g). C8H18N2O. 159.2 (M+1).
    Figure imgb0686
  • N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((2-(3-methoxypiperidin-1-yl)ethyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide was prepared analogously to Example 229 using 3-(2-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one and 2-(3-methoxypiperidin-1-yl)ethan-1-amine hydrochloride in place of 3-(2-chloro-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one and 3-aminopropanamide hydrochloride, respectively. C21H25ClFN7O2. 462.2 (M+H). 1H NMR (400 MHz, DMSO-d 6) δ 11.30 (s, 1H), 8.93 (s, 1H), 7.97 (d, J = 5.6 Hz, 0H), 7.09 (t, J = 9.1 Hz, 1H), 7.03 - 6.75 (m, 2H), 6.55 (ddd, J = 9.0, 3.9, 2.7 Hz, 1H), 3.88 - 3.02 (m, 14H), 2.00 - 1.54 (m, 2H).
    • Example 321: N-(3-chloro-4-fluorophenyl)-2-((3-(difluoromethoxy)propyl)amino)- N' -hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0687
  • Example 321 was prepared analogously to Example 333 using 3-(2-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one and 3-(difluoromethoxy)propan-1-amine in place of 3-(2-chloro-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one and tert-butyl (2-aminoethyl)carbamate, respectively. C17H16ClF3N6O2. 429.1 (M+H). 1H NMR (400 MHz, DMSO-d 6) δ 11.38 (s, 1H), 8.94 (s, 1H), 7.94 (d, J = 6.2 Hz, 1H), 7.08 (t, J = 9.0 Hz, 1H), 7.05 - 6.96 (m, 1H), 6.93 - 6.80 (m, 1H), 6.66 (t, J = 76.1 Hz, 1H), 6.56 (ddd, J = 8.8, 4.2, 2.8 Hz, 1H), 3.90 (t, J = 6.2 Hz, 2H), 3.55 - 3.45 (m, 2H), 1.96 - 1.83 (m, 2H).
    • Example 322: (R)-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(((tetrahydrofuran-2-yl)methyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0688
  • Example 322 was prepared analogously to Example 333 using 3-(2-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one and (R)-(-)-tetrahydrofurfurylamine in place of 3-(2-chloro-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one and tert-butyl (2-aminoethyl)carbamate, respectively. C18H18ClFN6O2. 405.2 (M+1).
    • Example 323: (S)-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(((tetrahydrofuran-2-yl)methyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0689
  • Example 323 was prepared analogously to Example 333 using 3-(2-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one and (S)-(+)-tetrahydrofurfurylamine in place of 3-(2-chloro-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one and tert-butyl (2-aminoethyl)carbamate, respectively. C18H18ClFN6O2. 405.2 (M+H). 1H NMR (400 MHz, DMSO-d 6) δ 11.45 (s, 1H), 8.97 (s, 1H), 7.98 (d, J = 6.3 Hz, 1H), 7.11 (t, J = 9.0 Hz, 1H), 7.04 (dd, J = 6.5, 2.8 Hz, 1H), 6.93 (d, J = 6.3 Hz, 1H), 6.60 (ddd, J = 8.9, 4.0, 3.0 Hz, 1H), 4.09 - 3.98 (m, 1H), 3.80 (dt, J = 8.2, 6.7 Hz, 1H), 3.68 (dt, J = 8.1, 6.8 Hz, 1H), 3.63 - 3.52 (m, 1H), 3.51 - 3.38 (m, 1H), 2.03 - 1.76 (m, 3H), 1.66 - 1.49 (m, 1H).
    • Example 324: N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((2-(tetrahydrofuran-2-yl)ethyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0690
  • Example 324 was prepared analogously to Example 333 using 3-(2-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one and 2-(oxolan-2-yl)ethan-1-amine in place of 3-(2-chloro-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one and tert-butyl (2-aminoethyl)carbamate, respectively. C19H20ClFN6O2. 419.2 (M+H). 1H NMR (400 MHz, DMSO-d 6) δ 11.38 (s, 1H), 8.96 (s, 1H), 7.95 (d, J = 6.1 Hz, 1H), 7.10 (t, J = 9.0 Hz, 1H), 7.03 (dd, J = 6.5, 2.7 Hz, 1H), 6.91 (d, J = 6.2 Hz, 1H), 6.58 (ddd, J = 9.0, 4.1, 3.0 Hz, 1H), 3.89 - 3.75 (m, 2H), 3.62 (td, J = 7.9, 6.4 Hz, 1H), 3.54 - 3.47 (m, 2H), 2.03 - 1.67 (m, 5H), 1.52 - 1.37 (m, 1H).
    • Example 325: N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(piperidin-2-ylmethyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0691
  • 2-(piperidin-2-ylmethyl)-1H-imidazo[4,5-b]pyridine-7-carboxylic acid. A suspension of 2,3-diaminoisonicotinic acid hydrochloride (200 mg, 0.106 mmol) and 2-(piperidin-2-yl)acetic acid (453 mg, 0.317 mmol) in sulfuric acid (1.5 mL) was stirred at room temperature for 5 min and, then, was sealed in a vial and stirred at 160 °C for 3 hours. Once the mixture had cooled, water (2 mL) was added and the solution was purified by preparative HPLC to give the desired product. C13H16N4O2. 261.1 (M+1).
    Figure imgb0692
  • 2-((1-(tert-butoxycarbonyl)piperidin-2-yl)methyl)-1H-imidazo[4,5-b]pyridine-7-carboxylic acid. A solution of 2-(piperidin-2-ylmethyl)-1H-imidazo[4,5-b]pyridine-7-carboxylic acid (205 mg, 0.788 mmol), di-tert-butyl dicarbonate (189 mg, 0.866 mmol), and triethylamine (0.440 ml, 3.15 mmol) in dichloromethane (8 mL) was stirred for 3 hr and concentrated to give the desired product. C18H24N4O4. 361.1 (M+1).
    Figure imgb0693
  • tert-butyl 2-((7-((3-chloro-4-fluorophenyl)carbamoyl)-1H-imidazo[4,5-b]pyridin-2-yl)methyl)piperidine-1-carboxylate. A solution of 2-((1-(tert-butoxycarbonyl)piperidin-2-yl)methyl)-1H-imidazo[4,5-b]pyridine-7-carboxylic acid (283 mg, 0.785 mmol), 4-fluoro-3-chloroaniline (171 mg, 1.18 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (388 mg, 1.02 mmol) and N,N-diisopropylethylamine (0.684 ml, 3.93 mmol) in dimethylformamide (1.5 mL) was stirred for 3 hours. The reaction mixture was concentrated and purified by preparative HPLC. The resulting lyophilized material was mixed with saturated aqueous sodium bicarbonate (5 mL), filtered, washed with water and dried on high vacuum to give the desired product. C24H27ClFN5O3. 488.1 (M+1).
    Figure imgb0694
  • N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(piperidin-2-ylmethyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide. To a mixture of tert-butyl 2-((7-((3-chloro-4-fluorophenyl)carbamoyl)-1H-imidazo[4,5-b]pyridin-2-yl)methyl)piperidine-1-carboxylate (100 mg, 0.205 mmol) and potassium carbonate (198 mg, 1.43 mmol) in dichloromethane (2 ml) was added phosphorous pentachloride (85 mg, 0.409 mmol). The reaction mixture stirred for 2 hours and was concentrated. The residue was brought up in ethanol (2 ml) and hydroxylamine (0.50 mL, 50% in water, 8 mmol) and stirred for 1 hour. The reaction mixture was concentrated and purified by preparative HPLC to give the desired product. C19H20ClFN6O. 403.1 (M+1).
    • Example 326: N-(3-chloro-4-fluorophenyl)-2-(1-(dimethylamino)propan-2-yl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0695
  • Example 326 was prepared analogously to Example 305 using 3-(dimethylamino)-2-methylpropanoic acid in place of 2-(1-methylpiperidin-2-yl)acetic acid. C18H20ClFN6O. 391.1 (M+1).
    • Example 327: N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(2-(methylamino)propyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0696
  • Example 327 was prepared analogously to Example 325 using 3-(methylamino)butanoic acid in place of 2-(piperidin-2-yl)acetic acid. C17H18ClFN6O. 377.1 (M+1).
    • Example 328: N-(3-chloro-4-fluorophenyl)-2-(2-(dimethylamino)propyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0697
  • Example 328 was prepared analogously to Example 305 using 3-(dimethylamino)butanoic acid in place of 2-(1-methylpiperidin-2-yl)acetic acid. C18H20ClFN6O. 391.1 (M+1).
    • Example 329: N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(pyrrolidin-2-ylmethyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0698
  • Example 329 was prepared analogously to Example 325 using 2-(pyrrolidin-2-yl)acetic acid in place of 2-(piperidin-2-yl)acetic acid. C18H18ClFN6O. 389.1 (M+1).
    • Example 330: N-(3-chlorophenyl)-4,5-difluoro-N'-hydroxy-2-((2-(pyrrolidin-1-yl)ethyl)amino)-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0699
  • Example 330 was prepared analogously to Example 39 using 2-(pyrrolidin-1-yl)ethanamine in place of N,N-dimethylpropane-1,3-diamine and 3-chloroaniline in place of 3-chloro-4-fluoroaniline. C20H21ClF2N6O. 435.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 11.02 - 10.85 (m, 1H), 10.79 (s, 1H), 9.83 - 9.63 (m, 1H), 8.68 (s, 1H), 7.03 (t, J = 8.0 Hz, 1H), 6.89 - 6.73 (m, 2H), 6.55 - 6.44 (m, 1H), 3.74 - 3.60 (m, 2H), 3.44 - 3.32 (m, 2H), 2.05 - 1.83 (m, 4H).
    • Example 331: N-(3-bromophenyl)-4,5-difluoro-N'-hydroxy-2-((2-(pyrrolidin-1-yl)ethyl)amino)-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0700
  • Example 331 was prepared analogously to Example 39 using 2-(pyrrolidin-1-yl)ethanamine in place of N,N-dimethylpropane-1,3-diamine and 3-bromoaniline in place of 3-chloro-4-fluoroaniline. C20H21BrF2N6O. 479.1 (M+1). NMR (400 MHz, DMSO-d6) δ 10.80 (s, 1H), 9.83 - 9.67 (m, 1H), 8.67 (s, 1H), 7.01 - 6.73 (m, 6H), 6.52 (dt, J = 7.7, 1.8 Hz, 1H), 3.71 - 3.59 (m, 2H), 3.42 - 3.32 (m, 2H), 1.93 (s, 4H).
    • Example 332: N-(3-bromo-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((2-(pyrrolidin-1-yl)ethyl)amino)-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0701
  • Example 332 was prepared analogously to Example 39 using 2-(pyrrolidin-1-yl)ethanamine in place of N,N-dimethylpropane-1,3-diamine and 3-bromo-4-fluoroaniline in place of N,N-dimethylpropane-1,3-diamine. C20H20BrF3N6O. 497.1 (M+1).
    • Example 333: 2-((2-aminoethyl)amino)-N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0702
  • Methyl 6,7-difluoro-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-4-carboxylate. A solution of methyl 2,3-diamino-4,5-difluorobenzoate (10 g, 50 mmol) and carbonyldiimidazole (12 g, 75 mmol) in THF (100 mL) was stirred overnight. Diethyl ether was added to the reaction mixture and the precipitate was filtered and dried on high vacuum to give the desired product. C9H6F2N2O3. 229.5 (M+1).
    Figure imgb0703
  • Methyl 2-chloro-4,5-difluoro-1H-benzo[d]imidazole-7-carboxylate. A mixture of methyl 6,7-difluoro-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-4-carboxylate (9.98 g, 43.7 mmol) in phosphoryl chloride (80 mL) was stirred overnight at 120 °C. The solution was cooled and concentrated. To the solid residue cooled in an ice bath was cautiously added a saturated aqueous sodium bicarbonate solution. The slurry was filtered and the filtrate was washed with water and dried on high vacuum to give the desired product. C9H5ClF2N2O2. 247.2 (M+1).
    Figure imgb0704
  • 2-chloro-N-(3-chloro-4-fluorophenyl)-4,5-difluoro-1H-benzo[d]imidazole-7-carboxamide. To a solution of the 3-chloro-4-fluoroaniline (4.43 g, 30 mmol) in dichloroethane (50 mL) at 0 °C was added a solution of trimethylaluminum (30.4 mL, 2 M in heptane, 61 mmol) dropwise over 5 min. The ice bath was removed and the mixture stirred for 30 minutes. The solution was cooled back down with and ice bath and methyl 2-chloro-4,5-difluoro-1H-benzo[d]imidazole-7-carboxylate (5 g, 20 mmol) was added to this solution as a solid. The reaction stirred at 60 °C for 6 hours. The reaction was cooled in an ice bath and to this cooled mixture was added 10% citric acid (30 mL). To this solution was added 2N sodium hydroxide and the aqueous layer was washed three times with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated to give the desired product. C14H6Cl2F3N3O. 360.5 (M+1).
    Figure imgb0705
  • 3-(2-chloro-4,5-difluoro-1H-benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one. A mixture of 2-chloro-N-(3-chloro-4-fluorophenyl)-4,5-difluoro-1H-benzo[d]imidazole-7-carboxamide (6.56 g, 18.2 mmol) and potassium carbonate (17.6 g, 127 mmol) in dichloromethane (100 mL) was stirred together for 5 min. To this mixture was added phosphorus pentachloride (7.58 g, 36 mmol) and the mixture stirred for two hours. More phosphorus penetachloride was added (7.58 g, 36 mmol) and the mixture stirred for another three hours. The reaction mixture was concentrated and placed in an ice bath. To the cooled residue was added a solution of hydroxyamine (44.5 mL, 50% in water, 728 mmol) and ethanol (100 mL) over 20 min. The ice bath was removed and the reaction stirred for 30 min. The reaction mixture was concentrated and brought up in water and washed three times with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated to about 50 ml. To this solution was added carbonyldiimidazole (5.9 g, 36 mmol). The reaction solution stirred for 30 min and was diluted with ethyl acetate and washed twice with 1 N hydrochloric acid and once with saturated aqueous sodium chloride. The organic layer was dried over sodium sulfate, filtered, and concentrated to give the desired product. C15H5Cl2F3N4O2. 401.0 (M+1).
    Figure imgb0706
  • 3-(2-chloro-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one. To a solution of 3-(2-chloro-4,5-difluoro-1H-benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one (7.3 g, 18 mmol) and triethylamine (15 mL, 109 mmol) in dichloromethane (200 mL) was added (2-(chloromethoxy)ethyl)trimethylsilanel (8 mL, 46 mmol). Reaction was stirred for 2 hr, and was adsorbed onto silica gel and purified by silica gel chromatography to give the desired product. C21H19C12F3N4O3Si. 554.9 (M+23).
    Figure imgb0707
  • 3-(2-((2-aminoethyl)amino)-4,5-difluoro-1H-benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one. A solution of 3-(2-chloro-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one (390 mg, 0.734 mmol), and tert-butyl (2-aminoethyl)carbamate (141 mg, 0.881 mmol) in dimethylsulfoxide (3.5 mL) was stirred at 65 °C overnight. The reaction mixture was cooled and diluted with ethyl acetate and washed three times with saturated aqueous sodium chloride. The organic layer was dried over sodium sulfate, filtered and concentrated. The resulting residue was brought up in dichloromethane (3 mL) and trifluoroacetic acid (3 mL) and stirred for 3 hours. The reaction solution was concentrated and brought up in saturated aqueous sodium bicarbonate and washed three times with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated to give the desired product (312 mg). C17H12ClF3N6O2. 425.2 (M+1).
    Figure imgb0708
  • 2-((2-aminoethyl)amino)-N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide. A solution of 3-(2-chloro-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one (29 mg, 0.056 mmol), and tert-butyl (2-aminoethyl)carbamate (44 mg, 0.27 mmol) in dimethylsulfoxide (0.2 mL) was stirred at 65 °C overnight. The reaction mixture was cooled and diluted with ethyl acetate and washed three times with saturated aqueous sodium chloride. The organic layer was dried over sodium sulfate, filtered and concentrated. The resulting residue was brought up in dichloromethane (0.5 mL) and trifluoroacetic acid (0.5 mL) and stirred for 3 hours. The reaction solution was concentrated. The resulting residue was brought up in tetrahydrofuran (0.2 mL) and methanol (0.2 mL) and to this solution was added 2 N sodium hydroxide (0.27 mL, 0.54 mmol). The resulting solution was stirred for 30 min and concentrated and purified by preparative HPLC to give the desired product. C16H14ClF3N6O. 399.1 (M+1).
    • Example 334: N-(2-((7-(N-(3-chloro-4-fluorophenyl)-N'-hydroxycarbamimidoyl)-4,5-difluoro-1H-benzo[d]imidazol-2-yl)amino)ethyl)acetamide
  • Figure imgb0709
  • To a solution of 3-(2-((2-aminoethyl)amino)-4,5-difluoro-1H-benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one (29 mg, 0.068 mmol) and triethylamine (0.048 mL, 0.34 mmol) in tetrahydrofuran (0.5 mL) was added acetyl chloride (0.007 mL, 0.10 mmol). The resulting solution stirred for one hour and was concentrated. The resulting residue was brought up in tetrahydrofuran (0.4 mL) and methanol (0.4 mL) and to this solution was added 2 N sodium hydroxide (0.34 mL, 0.68 mmol). The resulting solution was stirred for one hour, concentrated and purified by preparative HPLC to give the desired product (11 mg). C18H16ClF3N6O2. 441.1 (M+1).
    • Example 335: N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((2-(methylsulfonamido)ethyl)amino)-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0710
  • Example 335 was prepared analogously to Example 334 using methanesulfonyl chloride in place of acetyl chloride. C17H16ClF3N6O3S. 477.1 (M+1).
    • Example 336: N-(3-chloro-4-fluorophenyl)-2-((2-(cyclopropanesulfonamido)ethyl)amino)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0711
  • Example 336 was prepared analogously to Example 334 using cyclopropylsulfonyl chloride in place of acetyl chloride. C19H18ClF3N6O3S. 503.1 (M+1).
    • Example 337: Methyl (2-((7-(N-(3-chloro-4-fluorophenyl)-N'-hydroxycarbamimidoyl)-4,5-difluoro-1H-benzo[d]imidazol-2-yl)amino)ethyl)carbamate
  • Figure imgb0712
  • Example 337 was prepared analogously to Example 334 using methyl chloroformate in place of acetyl chloride. C18H16ClF3N6O3. 457.1 (M+1).
    • Examples 338: N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((2-(sulfamoylamino)ethyl)amino)-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0713
  • A solution of 3-(2-((2-aminoethyl)amino)-4,5-difluoro-1H-benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one (33 mg, 0.078 mmol) and sulfamide (75 mg, 0.78 mmol) was stirred at 110 °C for 20 min and was concentrated. The resulting residue was brought up in tetrahydrofuran (0.4 mL) and methanol (0.4 mL) and to this solution was added 2 N sodium hydroxide (0.38 mL, 0.76 mmol). The resulting solution was stirred for one hour, concentrated and purified by preparative HPLC to give the desired product. C16H15ClF3N7O3S. 478.1 (M+1).
    • Examples 339: N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((2-(phenylsulfonamido)ethyl)amino)-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0714
  • Example 339 was prepared analogously to Example 334 using benzenesulfonyl chloride in place of acetyl chloride. C22H18ClF3N6O3S. 539.1 (M+1).
    • Examples 340: N-(3-chloro-4-fluorophenyl)-2-((2-cyanoethyl)amino)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0715
  • Example 340 was prepared analogously to Example 333 using 3-aminopropanenitrile in place of tert-butyl (2-aminoethyl)carbamate. C17H12ClF3N6O. 409.4 (M+1).
    • Examples 341: N-(3-chloro-4-fluorophenyl)-2-((2-(3-ethylureido)ethyl)amino)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0716
  • Example 341 was prepared analogously to Example 334 using ethyl isocyanate in place of acetyl chloride. C19H19ClF3N7O2. 470.0 (M+1).
    • Examples 342: N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((pyridin-2-ylmethyl)amino)-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0717
  • Example 342 was prepared analogously to Example 333 using 2-picolylamine in place of tert-butyl (2-aminoethyl)carbamate. C20H14ClF3N6O. 447.2 (M+1).
    • Examples 343: N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((pyridin-3-ylmethyl)amino)-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0718
  • Example 343 was prepared analogously to Example 333 using 2-picolylamine in place of tert-butyl (2-aminoethyl)carbamate. C20H14ClF3N6O. 447.3 (M+1).
    • Example 344: N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((pyridin-3-ylmethyl)amino)-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0719
  • N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((pyridin-3-ylmethyl)amino)-1H-benzo[d]imidazole-7-carboximidamide. Example 344 was prepared analogously to Example 333 using 2-(1-methyl-1H-imidazol-2-yl)ethanamine in place of tert-butyl (2-aminoethyl)carbamate. C20H17ClF3N7O. 464.3 (M+1).
    • Examples 345 and 346: 2-(((1H-imidazol-2-yl)methyl)amino)-N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide and 2-chloro-N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0720
  • Example 345 was prepared analogously to Example 333 using (1H-imidazol-2-yl)methanamine dihydrochloride and diisopropylethylamine in place of tert-butyl (2-aminoethyl)carbamate. C18H13ClF3N7O. 436.3 (M+1). Unreacted 2-((2-aminoethyl)amino)-N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide through this sequence gave Example 346 (2-chloro-N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide). C14H7Cl2F3N4O. 375.1 (M+1).
    • Example 347: 2-((2-aminobenzyl)amino)-N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0721
  • Example 347 was prepared analogously to Example 333 using 2-(aminomethyl)aniline in place of tert-butyl (2-aminoethyl)carbamate. C21H16ClF3N6O. 461.1 (M+1).
    • Example 348: N-(3-chloro-4-fluorophenyl)-2-((2-(dimethylamino)benzyl)amino)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0722
  • Example 348 was prepared analogously to Example 333 using 2-(aminomethyl)-N,N-dimethylaniline in place of tert-butyl (2-aminoethyl)carbamate. C23H20ClF3N6O. 489.2 (M+1).
    • Example 349: N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-(((1-methyl-1H-imidazol-2-yl)methyl)amino)-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0723
  • Example 349 was prepared analogously to Example 333 using (1-methyl-1H-imidazol-2-yl)methanamine in place of tert-butyl (2-aminoethyl)carbamate. C19H15ClF3N7O. 450.1 (M+1).
    • Example 350: N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((pyrimidin-2-ylmethyl)amino)-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0724
  • Example 350 was prepared analogously to Example 333 using pyrimidin-2-ylmethanamine hydrochloride and diisopropylethylamine in place of tert-butyl (2-aminoethyl)carbamate. C19H13ClF3N7O. 448.1 (M+1).
    • Example 351: N-(3-chloro-4-fluorophenyl)-2-((3-(dimethylamino)-2,2-dimethylpropyl)amino)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0725
  • Example 351 was prepared analogously to Example 333 using N1,N1,2,2-tetramethylpropane-1,3-diamine in place of tert-butyl (2-aminoethyl)carbamate. C21H24ClF3N6O. 469.2 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 10.80 (s, 1H), 8.71 (s, 1H), 7.08 (t, J = 9.1 Hz, 1H), 6.91 (dd, J = 6.5, 2.7 Hz, 1H), 6.89 - 6.80 (m, 1H), 6.52 (ddd, J = 9.0, 4.0, 2.7 Hz, 1H), 3.33 (s, 2H), 2.98 (s, 2H), 2.85 (s, 6H), 1.03 (s, 6H).
    • Example 352: N-(3-chloro-4-fluorophenyl)-2-((3-(dimethylamino)-2-methylpropyl)amino)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0726
  • Example 352 was prepared analogously to Example 333 using N1,N1,2-trimethylpropane-1,3-diamine in place of tert-butyl (2-aminoethyl)carbamate. C20H22ClF3N6O. 455.2 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 10.80 (s, 1H), 8.74 (s, 1H), 7.07 (t, J = 9.1 Hz, 1H), 6.97 - 6.80 (m, 2H), 6.52 (dt, J = 8.2, 3.5 Hz, 1H), 3.38 - 3.25 (m, 2H), 3.02 - 2.61 (m, 8H), 2.31 - 2.16 (m, 1H), 1.01 - 0.89 (m, 3H).
    • Example 353: N-(3-chloro-4-fluorophenyl)-2-((3-(dimethylamino)butyl)amino)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0727
  • Example 353 was prepared analogously to Example 333 using N3,N3-dimethylbutane-1,3-diamine in place of tert-butyl (2-aminoethyl)carbamate. C20H22ClF3N6O. 455.2 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 10.78 (s, 1H), 8.71 (s, 1H), 7.07 (t, J = 9.1 Hz, 1H), 6.91 (dd, J = 6.6, 2.7 Hz, 1H), 6.89 - 6.79 (m, 1H), 6.52 (dt, J = 9.0, 3.4 Hz, 1H), 3.49 - 3.28 (m, 3H), 2.69 (d, J = 4.4 Hz, 6H), 2.01 (d, J = 11.7 Hz, 1H), 1.71 (dt, J = 14.1, 7.5 Hz, 1H), 1.22 (d, J = 6.5 Hz, 3H).
    • Example 354: N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((2-(1-methylpyrrolidin-2-yl)ethyl)amino)-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0728
  • Example 354 was prepared analogously to Example 333 using 2-(1-methylpyrrolidin-2-yl)ethanamine in place of tert-butyl (2-aminoethyl)carbamate. C21H22ClF3N6O. 467.2 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 10.79 (s, 1H), 9.55 (s, 1H), 8.70 (s, 1H), 7.07 (t, J = 9.1 Hz, 1H), 6.92 (dd, J = 6.5, 2.7 Hz, 1H), 6.89 - 6.81 (m, 1H), 6.51 (ddd, J = 9.0, 4.1, 2.8 Hz, 1H), 3.62 - 3.47 (m, 1H), 3.47 - 3.32 (m, 2H), 3.32 - 3.18 (m, 1H), 3.11 - 2.98 (m, 1H), 2.81 (d, J = 4.6 Hz, 3H), 2.34 - 2.09 (m, 2H), 2.05 - 1.69 (m, 3H), 1.68 - 1.57 (m, 1H).
    • Example 355: N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((2-(1-methylpiperidin-2-yl)ethyl)amino)-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0729
  • Example 355 was prepared analogously to Example 333 using 2-(1-methylpiperidin-2-yl)ethanamine in place of tert-butyl (2-aminoethyl)carbamate. C22H24ClF3N6O. 481.2 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 10.75 (s, 1H), 9.13 (s, 1h), 8.67 (s, 1H), 7.07 (t, J = 8.9 Hz, 1H), 6.93 - 6.88 (m, 1H), 6.80-6.74 (m, 1H), 6.55 - 6.49 (m, 1H), 2.85 - 2.81 (m, 2H), 2.80-2.75, (m, 2H), 2.56-2.6 (m, 1H), 2.52 (s, 3H), 1.83 - 1.35 (m, 8H).
    • Example 356: N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-(((4-methylmorpholin-2-yl)methyl)amino)-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0730
  • Example 356 was prepared analogously to Example 333 using (4-methylmorpholin-2-yl)methanamine in place of tert-butyl (2-aminoethyl)carbamate. C20H20ClF3N6O2. 469.2 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 10.79 (s, 1H), 9.89 (s, 1H), 8.67 (s, 1H), 7.09 (t, J = 9.1 Hz, 1H), 6.91 (dd, J = 6.5, 2.8 Hz, 1H), 6.81 (dd, J = 12.3, 6.9 Hz, 1H), 6.53 (ddd, J = 8.9, 4.1, 2.7 Hz, 1H), 4.07 (d, J = 12.7 Hz, 1H), 3.96 - 3.83 (m, 1H), 3.66 (t, J = 12.4 Hz, 1H), 3.59 - 3.32 (m, 4H), 3.10 - 2.95 (m, 1H), 2.90 - 2.80 (m, 4H).
    • Example 357: N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(((4-methylmorpholin-2-yl)methyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0731
  • Example 357 was prepared analogously to Example 333 using 3-(2-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one in place of 3-(2-chloro-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one and (4-methylmorpholin-2-yl)methanamine in place of tert-butyl (2-aminoethyl)carbamate. C19H21ClFN7O2. 434.2 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 11.38 (s, 1H), 10.18 (s, 1H), 8.93 (s, 1H), 7.96 (d, J = 6.2 Hz, 1H), 7.10 (t, J = 9.0 Hz, 1H), 6.99 (dd, J = 6.5, 2.8 Hz, 1H), 6.91 (d, J = 6.2 Hz, 1H), 6.58 (ddd, J = 9.0, 4.1, 2.8 Hz, 1H), 4.07 (d, J = 12.8 Hz, 1H), 3.90 (s, 1H), 3.73 - 3.34 (m, 5H), 3.08 - 2.94 (m, 1H), 2.92 - 2.77 (m, 4H).
    • Example 358: N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(((1-methyl-1H-pyrazol-5-yl)methyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0732
  • Example 358 was prepared analogously to Example 333 using 3-(2-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one in place of 3-(2-chloro-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one and (1-methyl-1H-pyrazol-5-yl)methanamine in place of tert-butyl (2-aminoethyl)carbamate. C18H16ClFN8O. 415.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 11.45 (s, 1H), 8.98 (s, 1H), 7.97 (d, J = 6.3 Hz, 1H), 7.32 (d, J = 1.9 Hz, 1H), 7.08 (t, J = 9.0 Hz, 1H), 7.04 (dd, J = 6.5, 2.7 Hz, 1H), 6.93 (d, J = 6.4 Hz, 1H), 6.61 - 6.53 (m, 1H), 6.18 (d, J = 1.9 Hz, 1H), 4.71 (d, J = 5.9 Hz, 2H), 3.83 (s, 3H).
    • Example 359: 2-((7-(N-(3-chloro-4-fluorophenyl)-N'-hydroxycarbamimidoyl)-1H-imidazo[4,5-b]pyridin-2-yl)amino)-N,N-dimethylacetamide
  • Figure imgb0733
  • Example 359 was prepared analogously to Example 333 using 3-(2-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one in place of 3-(2-chloro-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one and (4-methylmorpholin-2-yl)methanamine in place of tert-butyl (2-aminoethyl)carbamate. C17H17ClFN7O2. 406.2 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 11.43 (s, 1H), 8.95 (s, 1H), 7.98 (d, J = 6.2 Hz, 1H), 7.10 (t, J = 9.0 Hz, 1H), 7.02 (dd, J = 6.5, 2.7 Hz, 1H), 6.92 (d, J = 6.2 Hz, 1H), 6.58 (ddd, J = 8.9, 3.9, 2.7 Hz, 1H), 4.30 (d, J = 4.9 Hz, 2H), 2.98 (s, 3H), 2.89 (s, 3H).
    • Examples 360 and 361: N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(3-(hydroxymethyl)azetdin-1-yl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide and N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((oxetan-3-ylmethyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0734
  • Examples 360 and 361 were prepared analogously to Example 333 using 3-(2-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one in place of 3-(2-chloro-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one and oxetan-3-ylmethanamine in place of tert-butyl (2-aminoethyl)carbamate. C17H16ClFN6O2. 391.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 12.73 (s, 1H), 11.22 (s, 1H), 8.92 (s, 1H), 8.09 (s, 1H), 7.08 (t, J = 9.0 Hz, 1H), 7.03 (d, J = 5.4 Hz, 1H), 6.99 (dd, J = 6.4, 2.7 Hz, 1H), 6.53 (ddd, J = 9.0, 4.1, 2.8 Hz, 1H), 4.98 (s, 1H), 4.23 (dd, J = 12.4, 4.9 Hz, 1H), 3.78 (dd, J = 12.3, 8.6 Hz, 1H), 3.35 - 3.23 (m, 1H). C17H16ClFN6O2. 391.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 11.16 (s, 1H), 9.44-9.28 (m, 1H), 9.09 (s, 1H), 7.97-7.85 (m, 1H), 7.09 (dd, J = 6.5, 2.7 Hz, 1H), 7.04 (t, J = 9.0 Hz, 1H), 6.83 (s, 1H), 6.59 (dt, J = 8.9, 3.6 Hz, 1H), 4.26 (dd, J = 12.3, 4.8 Hz, 1H), 3.91 - 3.81 (m, 1H), 3.25 (t, J = 10.9 Hz, 1H).
    • Example 362: N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((2-(1-methyl-1H-imidazol-2-yl)ethyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0735
  • Example 362 was prepared analogously to Example 333 using 3-(2-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one in place of 3-(2-chloro-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one and 2-(1-methyl-1H-imidazol-2-yl)ethanamine in place of tert-butyl (2-aminoethyl)carbamate. C19H18ClFN8O.429.2 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 11.36 (s, 1H), 8.96 (s, 1H), 7.97 (d, J = 6.2 Hz, 1H), 7.58 (d, J = 2.0 Hz, 1H), 7.54 (d, J = 2.0 Hz, 1H), 7.08 (t, J = 9.0 Hz, 1H), 6.99 (dd, J = 6.5, 2.7 Hz, 1H), 6.94 (d, J = 6.2 Hz, 1H), 6.60 - 6.50 (m, 1H), 3.83 - 3.68 (m, 5H), 3.31 - 3.21 (m, 2H).
    • Example 363: N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((3-(pyridin-2-ylamino)propyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0736
  • Example 363 was prepared analogously to Example 333 using 3-(2-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one in place of 3-(2-chloro-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one and N1-(pyridin-2-yl)propane-1,3-diamine in place of tert-butyl (2-aminoethyl)carbamate. C21H20ClFN8O.455.2 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 11.34 (s, 1H), 8.95 (s, 1H), 7.95 (d, J = 6.2 Hz, 1H), 7.92 (d, J = 6.2 Hz, 1H), 7.85 - 7.74 (m, 1H), 7.08 (t, J = 9.0 Hz, 1H), 7.01 (dd, J = 6.5, 2.7 Hz, 1H), 6.91 (d, J = 6.2 Hz, 1H), 6.84 - 6.72 (m, 1H), 6.56 (dt, J = 9.0, 4.0, 3.0 Hz, 1H), 3.56 - 3.44 (m, 2H), 3.42 - 3.31 (m, 2H), 1.96 - 1.83 (m, 2H).
    • Example 364: N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(neopentylamino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0737
  • Example 364 was prepared analogously to Example 333 using 3-(2-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one in place of 3-(2-chloro-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one and isopentylamine in place of tert-butyl (2-aminoethyl)carbamate. C18H20ClFN6O. 391.2 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 11.41 (s, 1H), 8.95 (s, 1H), 7.95 (d, J = 6.3 Hz, 1H), 7.09 (t, J = 8.9 Hz, 1H), 7.03 (dd, J = 6.6, 2.7 Hz, 1H), 6.91 (d, J = 6.2 Hz, 1H), 6.62 - 6.53 (m, 1H), 3.27 (d, J = 6.3 Hz, 2H), 0.92 (s, 9H).
    • Example 365: N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(isobutylamino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0738
  • Example 365 was prepared analogously to Example 333 using 3-(2-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one in place of 3-(2-chloro-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one and isobutylamine in place of tert-butyl (2-aminoethyl)carbamate. C17H18ClFN6O. 377.2 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 11.38 (s, 1H), 8.95 (s, 1H), 7.95 (d, J = 6.2 Hz, 1H), 7.08 (t, J = 9.0 Hz, 1H), 7.03 (dd, J = 6.6, 2.7 Hz, 1H), 6.91 (d, J = 6.2 Hz, 1H), 6.61 - 6.51 (m, 1H), 3.29 - 3.18 (m, 2H), 1.95 - 1.78 (m, 1H), 0.90 (d, J = 6.7 Hz, 6H).
    • Example 366: N-(3-chloro-4- fluorophenyl)-N'-hydroxy-2-(((tetrahydro-2H-pyran-2-yl)methyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0739
  • Example 366 was prepared analogously to Example 333 using 3-(2-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one in place of 3-(2-chloro-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one and (tetrahydro-2H-pyran-2-yl)methanamine in place of tert-butyl (2-aminoethyl)carbamate. C19H20ClFN6O2. 419.2 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 11.43 (s, 1H), 8.95 (s, 1H), 7.95 (d, J = 6.4 Hz, 1H), 7.10 (t, J = 9.0 Hz, 1H), 7.02 (dd, J = 6.5, 2.7 Hz, 1H), 6.90 (d, J = 6.3 Hz, 1H), 6.62 - 6.54 (m, 1H), 3.91 (d, J = 11.2 Hz, 1H), 3.57 - 3.43 (m, 2H), 3.44 - 3.30 (m, 2H), 1.84 - 1.71 (m, 1H), 1.58 (d, J = 12.7 Hz, 1H), 1.54 - 1.38 (m, 3H), 1.30 - 1.14 (m, 1H).
    • Example 367: N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(((tetrahydrofuran-3-yl)methyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0740
  • Example 367 was prepared analogously to Example 333 using 3-(2-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one in place of 3-(2-chloro-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one and (tetrahydrofuran-3-yl)methanamine in place of tert-butyl (2-aminoethyl)carbamate. C18H18ClFN6O2. 405.2 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 11.38 (s, 1H), 8.96 (s, 1H), 7.95 (d, J = 6.3 Hz, 1H), 7.08 (t, J = 9.0 Hz, 1H), 7.03 (dd, J = 6.5, 2.7 Hz, 1H), 6.91 (d, J = 6.2 Hz, 1H), 6.59 - 6.53 (m, 1H), 3.75 (td, J = 8.1, 5.6 Hz, 1H), 3.68 (dd, J = 8.6, 7.0 Hz, 1H), 3.62 (td, J = 8.0, 6.7 Hz, 1H), 3.47 (dd, J = 8.7, 5.1 Hz, 1H), 3.43 - 3.36 (m, 2H), 2.00 - 1.90 (m, 1H), 1.58 (dq, J = 12.8, 6.4, 6.3 Hz, 1H).
    • Example 368: N-(3-chloro-4- fluorophenyl)-4-fluoro-N'-hydroxy-2-((2-morpholinoethyl)amino)-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0741
  • Methyl 2,3-diamino-4-fluorobenzoate (0.150 g, 0.814 mmol) was dissolved in THF (4.0 mL) and 4-(2-isothiocyanatoethyl)morpholine (5.0 mmol) and triethylamine (7.0 mmol) was added. The reaction was sealed in a vial and heated to 66 °C for 12 hours. 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (5.0 mmol) was added in one portion and the reaction was allowed to heat an additional 1 hour at 66 °C. The reaction was cooled to rt and quenched with saturated sodium bicarbonate solution (4 mL). The reaction mixture was extracted with EtOAc (3 x 3 mL) and the combined organic layers were washed once with water, concentrated, and purified by silica gel column chromatography (0-15% MeOH/CH2Cl2, Rf= 0.33 in 10% MeOH/ CH2Cl2) to give methyl 4-fluoro-2-((2-morpholinoethyl)amino)-1H-benzo[d]imidazole-7-carboxylate.
  • Methyl 4-fluoro-2-((2-morpholinoethyl)amino)-1H-benzo[d]imidazole-7-carboxylate (0.208g, 0.645 mmol) and 3-chloro-4-fluoroaniline (3.0 mmol) were dissolved in DCE (6.0 mL) under inert conditions. Trimethylaluminium (5.0 mmol, 2.26 mL) was added at 0 C and the reaction was then heated to 60 C overnight. The reaction was allowed to cool to rt, quenched with water (3 mL) and extracted with EtOAc (4 x 3 mL). The combined organic layers were washed once with water, concentrated, and purified by silica gel chromatography (Rf= 0.37 10% MeOH/DCM) to give the desired product.
    Figure imgb0742
  • N-(3-chloro-4-fluorophenyl)-4-fluoro-N'-hydroxy-2-((2-morpholinoethyl)amino)-1H-benzo[d]imidazole-7-carboximidamide was made analogously to Example 10 using the procedure for hydroxyamidine formation. C20H21ClF2N6O2. 451.8 (M+1).
    • Example 369: N-(3-chloro-4-fluorophenyl)-N'-hydroxy-N-methyl-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0743
  • 1H-imidazo[4,5-b]pyridine-7-carboxylic acid (0.20 g, 1.22 mmol) and 3-chloro-4-fluoro-N-methylaniline hydrochloride (1.02 mmol) were dissolved in DMF (3.0 mL) and HATU (1.2 mmol) and DIPEA (2.78 mmol) were added and the reaction was allowed to stir overnight at rt. The reaction was quenched with sat/ sodium bicarbonate solution (3.0 mL) and the reaction was extracted with EtOAc (3 2 mL). Combined organic layers were washed with water (1x 4 mL) and the crude was purified by silica gel chromatography (Rf=0.25 50% EtOAc/hex) to give N-(3-chloro-4-fluorophenyl)-N-methyl-1H-imidazo[4,5-b]pyridine-7-carboxamide.
  • N-(3-chloro-4-fluorophenyl)-N-methyl-1H-imidazo[4,5-b]pyridine-7-carboxamide (0.05g, 0.164 mmol) was dissolved in toluene (3.0 mL) and Lawesson's reagent (0.656 mmol) was added. The reaction was sealed in a vial and heated overnight at 100 C. The reaction was then cooled to rt and solids were removed by vacuum filtration. The filtrate was concentrated and purified by silica gel chromatography to give N-(3-chloro-4-fluorophenyl)-N-methyl-1H-imidazo[4,5-b]pyridine-7-carbothioamide.
    Figure imgb0744
  • N-(3-chloro-4-fluorophenyl)-N-methyl-1H-imidazo[4,5-b]pyridine-7-carbothioamide (0.014 g, 0.0455 mmol) was dissolved in ethanol (3.0 mL) and hydroxylamine (50% solution in water) (0.455 mmol) was added and the reaction was allowed to stir at rt overnight. The reaction was concentrated to dryness then purified by RP HPLC to give N-(3-chloro-4-fluorophenyl)-N'-hydroxy-N-methyl-1H-imidazo[4,5-b]pyridine-7-carboximidamide (3.1 mg, 21%). C14H11ClFN5O. 320.7 (M+1).
    • Example 370: 2-amino-N-(3-chloro-4-fluorophenyl)-5-fluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0745
  • 2,3-diamino-5-fluorobenzoic acid (5.0 g, 29 mmol) was dissolved in sulfuric acid (5.0 mL) and MeOH (40.0 mL) and heated to 71 C overnight. The reaction was allowed to cool to rt then concentrated to approximately half the volume. The reaction was neutralized to pH=7 with saturated sodium carbonate solution then extracted with EtOAc (5 x 20 mL). Combined organic layers were washed once with water and concentrated to dryness to give methyl 2,3-diamino-5-fluorobenzoate.
  • Methyl 2,3-diamino-5-fluorobenzoate (2.0 g, 11.0 mmol) and cyanogen bromide (11.0 mmol) were dissolved in methanol (45 mL) and water (20 mL) and heated to 70 C for 30 mins. The reaction was cooled to rt and diluted with water (5 mL) and EtOAc (20 mL). The water layer was separated and neutralized to pH=7 with saturated sodium carbonate solution then extracted with EtOAc (4 x 10 mL). The combined organic layers were washed once with water then concentrated to give methyl 2-amino-5-fluoro-1H-benzo[d]imidazole-7-carboxylate.
  • Methyl 2-amino-5-fluoro-1H-benzo[d]imidazole-7-carboxylate (0.2g, 0.956 mmol) and 3-chloro-4-fluoroaniline (4.0 mmol) were dissolved in DCE (3.0 mL) and cooled to 0 C under an inert atmosphere. Trimethylaluminium (7.0 mmol, 3.34 mL) was added and the reaction was slowly heated to 65 C overnight. The reaction was cooled to rt, quenched with water (3 mL) and extracted with EtOAc (3 x 5 mL). Combined organic layers were washed once with water and purified by silica gel chromatography (Rf 100% EtOAc = 0.32) to give 2-amino-N-(3-chloro-4-fluorophenyl)-5-fluoro-1H-benzo[d]imidazole-7-carboxamide.
    Figure imgb0746
  • 2-amino-N-(3-chloro-4-fluorophenyl)-5-fluoro-1H-benzo[d]imidazole-7-carboxamide and Lawesson's reagent (3.0 mmol) were dissolved in toluene and heated overnight at 100 C. The reaction was allowed to cool to rt and the solids were removed by filtration. The filtrate was concentrated and used directly in the next reaction with no further purification.
  • 2-amino-N-(3-chloro-4-fluorophenyl)-5-fluoro-1H-benzo[d]imidazole-7-carbothioamide (0.267 g, 0.788 mmol) was dissolved in ethanol (3 mL) and hydroxylamine (50% solution in water) (0.5 mL) was added and the reaction was allowed to stir overnight at rt. The reaction was concentrated and purified by RP HPLC to give 2-amino-N-(3-chloro-4-fluorophenyl)-5-fluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide. C14H10ClF2N5O. 338.1 (M+1).
    • Example 371: 2-amino-N-(3-chlorophenyl)-5-fluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0747
  • Example 371 was made analogously to Example 370 using 3-chloroaniline in place of 3-chloro-4-fluoroaniline. C14H11ClFN5O. 320.7 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 12.05 (s, 1H), 11.10 (s, 1H), 8.83 (s, 1H), 8.26 (s, 2H), 7.26 (dd, J = 8.3, 2.4 Hz, 1H), 7.06 (t, J = 8.3 Hz, 1H), 6.91 (dd, J = 10.5, 2.4 Hz, 1H), 6.88 - 6.83 (m, 2H), 6.57 - 6.48 (m, 1H).
    • Example 372: 2-amino-N-(3-bromophenyl)-5-fluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0748
  • Example 372 was made analogously to Example 370 using 3-bromoaniline in place of 3-chloro-4-fluoroaniline. C14H11BrFN5O. 365.2 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 12.05 (s, 1H), 11.10 (s, 1H), 8.82 (s, 1H), 8.27 (s, 2H), 7.26 (dd, J = 8.3, 2.4 Hz, 1H), 7.04 - 6.95 (m, 3H), 6.91 (dd, J = 10.5, 2.4 Hz, 1H), 6.60 - 6.51 (m, 1H).
    • Example 373: 2-amino-N-(3-bromo-4-fluorophenyl)-5-fluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0749
  • Example 373 was made analogously to Example 370 using 3-bromo-4-fluoroaniline in place of 3-chloro-4-fluoroaniline. C14H10BrF2N5O. 383.2 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 12.11 (s, 1H), 11.03 (s, 1H), 8.79 (s, 1H), 8.36 - 8.23 (m, 2H), 7.26 (dd, J = 8.3, 2.4 Hz, 1H), 7.13 - 7.04 (m, 2H), 6.92 (dd, J = 10.5, 2.4 Hz, 1H), 6.60 (ddd, J = 8.9, 4.2, 2.8 Hz, 1H).
    • Example 374: N-(3-chloro-4-fluorophenyl)-2-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0750
  • Example 374 was made analogously to Example 32 using 4-(2-aminoethyl)thiomorpholine 1,1-dioxide. C20H20ClF3N6O3S. 517.9 (M+1).
    • Example 375: N-(3-chloro-4-fluorophenyl)-2-((2-(diethylamino)ethyl)amino)-4-fluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0751
  • N1,N1-diethylethane-1,2-diamine (0.50 g, 4.0 mmol) and sodium bicarbonate (86 mmol) were dissolved in DCM (12.0 mL) under argon. Thiophosgene (17.0 mmol) was added dropwise and the reaction was allowed to stir at rt for 2 hours. DCM (10 mL) and water (10 mL) were added and the water layer was extracted with DCM (2 x 8 mL). Combined organic layers were washed with water (1 x 20 mL) and concentrated to a volume of 5 mL to give N,N-diethyl-2-isothiocyanatoethan-1-amine which was used without further purification.
  • N-(3-chloro-4-fluorophenyl)-2-((2-(diethylamino)ethyl)amino)-4-fluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide was made analogously to Example 23 using N,N-diethyl-2-isothiocyanatoethan-1-amine, methyl 2,3-diamino-4-fluorobenzoate, and 3-chloro-4-fluoroaniline. C20H22ClF3N6O. 437.9 (M+1).
    • Example 376: N-(3-chloro-4-fluorophenyl)-4-fluoro-N'-hydroxy-2-((2-(pyrrolidin-1-yl)ethyl)amino)-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0752
  • Example 376 was made analogously to Example 375 using 2-(pyrrolidin-1-yl)ethan-1-amine in place of N1,N1-diethylethane-1,2-diamine. C20H21ClF2N6O. 435.8 (M+1).
    • Example 377: N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((2-morpholinopropyl)amino)-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0753
  • Example 377 was made analogously to Example 32 using 2-morpholinopropan-1-amine. C21H22ClF3N6O2. 483.9 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 10.82 (s, 1H), 8.71 (s, 1H), 7.17 (s, 1H), 7.09 (td, J = 9.1, 2.4 Hz, 2H), 6.94 (dd, J = 6.5, 2.7 Hz, 1H), 6.88 (dd, J = 12.2, 6.9 Hz, 1H), 6.78 (d, J = 6.4 Hz, 1H), 6.60 (d, J = 9.1 Hz, 1H), 6.54 (ddd, J = 9.0, 4.1, 2.7 Hz, 1H), 3.89 (s, 4H), 3.72 (s, 1H), 3.69 - 3.55 (m, 2H), 3.37 (s, 4H), 1.29 (d, J = 6.6 Hz, 3H).
    • Example 378: N-(3-chloro-4-fluorophenyl)-2-((1-(dimethylamino)propan-2-yl)amino)-4,5-difluoro-N-hydroxy-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0754
  • Exampl 378 was made analogously to Example 23 using N1,N1-dimethylpropane-1,2-diamine. C19H20ClF3N6O. 441.8 (M+1).
    • Example 379: N-(3-chloro-4-fluorophenyl)-2-((2-(dimethylamino)ethyl)amino)-5-fluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0755
  • Example 379 was made analogously to Example 23 using methyl 2,3-diamino-5-fluorobenzoate and 2-isothiocyanato-N,N-dimethylethan-1-amine. C18H19ClF2N6O. 409.8 (M+1). 1H NMR (400 MHz, Methanol-d4) δ 7.19 (dd, J = 8.1, 2.4 Hz, 1H), 6.97 (t, J = 8.9 Hz, 1H), 6.94 - 6.89 (m, 2H), 6.69 (dt, J = 8.8, 3.4 Hz, 1H), 3.85 (d, J = 5.8 Hz, 3H), 3.46 (dd, J = 12.2, 6.4 Hz, 3H), 2.99 (s, 6H).
    • Example 380: N-(3-chloro-4-fluorophenyl)-5-fluoro-N'-hydroxy-2-((2-(pyrrolidin-1-yl)ethyl)amino)-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0756
  • Example 380 was made analogously to Example 375 using 1-(2-isothiocyanatoethyl)pyrrolidine. C20H21ClF2N6O. 435.8 (M+1).
    • Example 381: N-(3-chloro-4-fluorophenyl)-2-((3-(dimethylamino)-2,2-dimethylpropyl)amino)-4-fluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0757
  • Example 381 was made analogously to Example 23 using methyl 2,3-diamino-4-fluorobenzoate and 3-isothiocyanato-N,N,2,2-tetramethylpropan-1-amine (made from N1,N1,2,2-tetramethylpropane-1,3-diamine). C21H25ClF2N6O. 451.9 (M+1).
    • Example 382: N-(3-bromo-4-fluorophenyl)-2-((2-(dimethylamino)ethyl)amino)-4-fluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0758
  • Example 382 was made analogously to Example 23 using methyl 2,3-diamino-4-fluorobenzoate, 2-isothiocyanato-N,N-dimethylethan-1-amine, and 3-bromo-4-fluoroaniline. C18H19BrF2N6O. 454.3 (M+1). 1H NMR (400 MHz, Methanol-d4) δ 7.41 (dd, J = 6.0, 2.4 Hz, 1H), 7.36 (dd, J = 8.7, 4.4 Hz, 1H), 7.16 (dd, J = 9.9, 8.7 Hz, 1H), 7.09 - 7.01 (m, 2H), 3.94 (t, J = 5.9 Hz, 2H), 3.52 (t, J = 6.0 Hz, 2H), 3.01 (s, 6H).
    • Example 383: N-(3-bromophenyl)-2-((2-(dimethylamino)ethyl)amino)-4-fluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0759
  • Example 383 was made analogously to Example 23 using methyl 2,3-diamino-4-fluorobenzoate, 2-isothiocyanato-N,N-dimethylethan-1-amine, and 3-bromoaniline. C18H20BrFN6O. 436.3 (M+1). 1H NMR (400 MHz, Methanol-d4) δ 7.33 (dd, J = 8.8, 4.5 Hz, 1H), 7.26 (d, J = 8.4 Hz, 2H), 7.19 - 7.06 (m, 2H), 6.93 (d, J = 8.6 Hz, 1H), 3.92 (t, J = 6.0 Hz, 2H), 3.51 (t, J = 6.0 Hz, 2H), 3.01 (s, 6H).
    • Example 384: N-(3-chlorophenyl)-2-((2-(dimethylamino)ethyl)amino)-4-fluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0760
  • Example 384 was made analogously to Example 23 using methyl 2,3-diamino-4-fluorobenzoate, 2-isothiocyanato-N,N-dimethylethan-1-amine, and 3-chloroaniline. C18H20ClFN6O. 391.8 (M+1). 1H NMR (400 MHz, Methanol-d4) δ 7.39 (dd, J = 8.7, 4.4 Hz, 1H), 7.22 - 7.01 (m, 5H), 6.94 (dq, J = 7.1, 2.3 Hz, 1H), 3.94 (t, J = 6.0 Hz, 2H), 3.52 (t, J = 6.1 Hz, 3H), 3.00 (s, 6H).
    • Example 385: N-(3-chlorophenyl)-2-((3-(dimethylamino)propyl)amino)-4,5-difluoro-N-hydroxy-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0761
  • Example 385 was made analogously to Example 32 using methyl 2-chloro-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-7-carboxylate, N1,N1-dimethylpropane-1,3-diamine, and 3-chloroaniline. C19H21ClF2N6O. 423.9 (M+1). 1HNMR (400 MHz, DMSO-d6) δ 10.88 (s, 1H), 9.69 (s, 1H), 8.74 (s, 1H), 7.05 (t, J = 8.3 Hz, 1H), 6.95 - 6.78 (m, 3H), 6.52 (dt, J = 8.3, 1.6 Hz, 1H), 3.42 (d, J = 6.4 Hz, 2H), 3.09 (d, J = 10.5 Hz, 2H), 2.80 (d, J = 4.4 Hz, 6H), 1.94 (p, J = 6.8 Hz, 2H).
    • Example 386: N-(3-bromophenyl)-2-((3-(dimethylamino)propyl)amino)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0762
  • Example 386 was made analogously to Example 32 using methyl 2-chloro-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-7-carboxylate, N1,N1-dimethylpropane-1,3-diamine, and 3-bromoaniline. C19H21BrF2N6O. 468.3 (M+1). 1H NMR (400 MHz, Methanol-d4) δ 7.37 - 7.27 (m, 1H), 7.10 - 6.99 (m, 3H), 6.69 (ddd, J = 8.0, 2.2, 1.1 Hz, 1H), 3.57 (t, J = 6.6 Hz, 2H), 3.28 - 3.21 (m, 2H), 2.93 (s, 6H), 2.18-2.08 (m, 2H).
    • Example 387: N-(3-bromo-4-fluorophenyl)-2-((3-(dimethylamino)propyl)amino)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0763
  • Example 387 was made analogously to Example 32 using methyl 2-chloro-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-7-carboxylate, N1,N1-dimethylpropane-1,3-diamine, and 3-bromo-4-fluoroaniline. C19H20BrF3N6O. 486.3 (M+1). 1H NMR (400 MHz, Methanol-d4) δ 7.14 - 7.04 (m, 2H), 6.96 (t, J = 8.6 Hz, 1H), 6.74 (ddd, J = 8.9, 4.0, 2.7 Hz, 1H), 3.56 (t, J = 6.6 Hz, 2H), 3.28 - 3.21 (m, 2H), 2.93 (s, 6H), 2.17 - 2.09 (m, 2H).
    • Example 388: N-(3-chloro-4-fluorophenyl)-2-((3-(dimethylamino)propyl)amino)-4-fluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0764
  • Example 388 was made analogously to Example 23 using methyl 2,3-diamino-4-fluorobenzoate and 3-isothiocyanato-N,N-dimethylpropan-1-amine. C19H21ClF2N6O. 423.8 (M+1) 1H NMR (400 MHz, Methanol-d4) δ 7.44 (dd, J = 8.8, 4.3 Hz, 1H), 7.39 (dd, J = 6.4, 2.3 Hz, 1H), 7.23 (dd, J = 9.8, 8.8 Hz, 1H), 7.15 - 7.05 (m, 2H), 3.62 (t, J = 6.8 Hz, 2H), 3.34 - 3.30 (m, 2H), 2.17 (t, J = 8.0 Hz, 2H).
    • Example 389: N-(3-chloro-4-fluorophenyl)-2-((3-(dimethylamino)propyl)amino)-5-fluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0765
  • Example 389 was made analogously to Example 23 using methyl 2,3-diamino-5-fluorobenzoate, 3-isothiocyanato-N,N-dimethylpropan-1-amine, and 3-chloro-4-fluoroaniline. C19H21ClF2N6O. 423.8 (M+1).
    • Example 390: 2-((2-(benzyl(methyl)amino)ethyl)amino)-N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0766
  • Example 390 was made analogously to Example 32 using N1-benzyl-N1-methylethane-1,2-diamine. C24H22ClF3N6O. 503.9 (M+1).
    • Example 391: N-(3-chloro-4-fluorophenyl)-2-(2-((cyclohexylmethyl)(methyl)amino)ethyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0767
  • Example 391 was made analogously to Example 184 using N-(3-chloro-4-fluorophenyl)-2-(2-hydroxyethyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide and 1-cyclohexyl-N-methylmethanamine. C23H28ClFN6O. 459.9 (M+1).
    • Example 392: N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(2-(methyl(neopentyl)amino)ethyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0768
  • Example 392 was made analogously to Example 184 using N,2,2-trimethylpropan-1-amine hydrochloride. C21H26ClFN6O. 434.1 (M+1).
    • Example 393: N-(3-chloro-4-fluorophenyl)-2-(2-(cyclohexyl(methyl)amino)ethyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0769
  • Example 393 was made analogously to Example 184 using N-methylcyclohexanamine. C22H26ClFN6O. 445.9 (M+1).
    • Example 394: N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((2-(methyl((tetrahydro-2H-pyran-4-yl)methyl)amino)ethyl)amino)-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0770
  • Methyl 2-chloro-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-7-carboxylate (1.39 g, 4.0 mmol) and tert-butyl (2-aminoethyl)(methyl)carbamate (6.0 mmol) were dissolved in DMSO (5.0 mL) and heated overnight at 60 C. The reaction was allowed to cool to rt and quenched with water (3 mL). The reaction was extracted with EtOAc (5 x 3mL) and combined organic layers were washed once with water and purified by silica gel column chromatography to give methyl 2-((2-((tert-butoxycarbonyl)(methyl)amino)ethyl)amino)-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-7-carboxylate.
  • Methyl 2-((2-((tert-butoxycarbonyl)(methyl)amino)ethyl)amino)-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-7-carboxylate (1.14 g, 2.0 mmol) and 3-chloro-4-fluoroaniline (9.0 mmol) were dissolved in DCE (15.0 mL) under an inert atmosphere. Triemthylaluminium (9.0 mmol, 4.430 mL) was added at 0 C and the reaction was allowed to come to rt and stir overnight. The reaction was quenched with water (5 mL) and extracted with DCM (3 x 6 mL). Combined organic layers were washed with water (1 x 8 mL) and concentrated to dryness. The crude was dissolved in DCM (8 mL) and TFA (4 mL) was added and the reaction was allowed to stir at rt for 1 hour. The reaction was concentrated and purified by silica gel chromatography to give N-(3-chloro-4-fluorophenyl)-4,5-difluoro-2-((2-(methylamino)ethyl)amino)-1H-benzo[d]imidazole-7-carboxamide.
    Figure imgb0771
  • N-(3-chloro-4-fluorophenyl)-4,5-difluoro-2-((2-(methylamino)ethyl)amino)-1H-benzo[d]imidazole-7-carboxamide (0.053 g, 0.132 mmol) and tetrahydro-2H-pyran-4-carbaldehyde (0.126 mmol) were dissolved in DCE (2.0 mL) under inert conditions. Sodium triacetoxyborohydride (STAB) (0.176 mmol) was added and the reaction was allowed to stir for 2 hours at rt. The reaction was quenched with water (3 mL) and then extracted with DCM (3 x 4 mL). Combined organic layers were washed once with water, dried over Mg2SO4, filtered, and concentrated to give N-(3-chloro-4-fluorophenyl)-4,5-difluoro-2-((2-(methyl((tetrahydro-2H-pyran-4-yl)methyl)amino)ethyl)amino)-1H-benzo[d]imidazole-7-carboxamide, which was then converted to N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((2-(methyl((tetrahydro-2H-pyran-4-yl)methyl)amino)ethyl)amino)-1H-benzo[d]imidazole-7-carboximidamide using hydroxyamidine formation conditions described herein. C23H26ClF3N6O2. 512.0 (M+1). 1H NMR (400 MHz, Methanol-d4) δ 7.45 (s, 1H), 6.95 (t, J = 8.9 Hz, 1H), 6.86 (td, J = 7.4, 4.9 Hz, 2H), 6.66 - 6.60 (m, 1H), 3.90 - 3.81 (m, 2H), 3.75 (t, J = 5.1 Hz, 2H), 3.43 (d, J = 5.9 Hz, 2H), 3.41 - 3.35 (m, 2H), 3.14 (d, J = 7.1 Hz, 2H), 3.00 (s, 3H), 1.71 (d, J = 13.0 Hz, 2H), 1.43 - 1.26 (m, 3H).
    • Example 395: N-(3-chloro-4- fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((2-(methylamino)ethyl)amino)-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0772
  • 3-(2-chloro-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one (0.03 g, 0.0565 mmol) and tert-butyl (2-aminoethyl)(methyl)carbamate (0.0847 mmol) were dissolved in DMS (0.6 mL) and heated overnight at 60 C. The reaction was cooled to rt, diluted with water, and extracted with DCM (3 x 1 mL). Combined organic layers were washed once with water and concentrated to give tert-butyl (2-((7-(4-(3-chloro-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)amino)ethyl)(methyl)carbamate which was used without further purification.
  • Tert-butyl (2-((7-(4-(3-chloro-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)amino)ethyl)(methyl)carbamate (0.057 mmol) was dissolved in DCM (2 mL) and TFA (1.0 mL) was added and the reaction was allowed to stir at rt for 2 hours before being concentrated to dryness. The residue was then dissolved in MeOH (2.0 mL) and 1M NaOH (0.5 mL) was added and the reaction was allowed to stir at rt for 30 mins. The reaction was then concentrated and purified by RP HPLC to N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((2-(methylamino)ethyl)amino)-1H-benzo[d]imidazole-7-carboximidamide. C17H16ClF3N6O. 413.8 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 10.72 (s, 1H), 8.65 (s, 1H), 8.50 (s, 2H), 6.98 (t, J = 9.1 Hz, 1H), 6.85 - 6.80 (m, 1H), 6.76 (s, 1H), 6.42 (dt, J = 8.9, 3.4 Hz, 1H), 3.52 (d, J = 5.8 Hz, 2H), 3.04 (t, J = 5.9 Hz, 2H), 2.50 (t, J = 5.3 Hz, 3H).
    • Example 396: 2-(2-(benzyl(methyl)amino)ethyl)-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0773
  • Example 396 was made analogously to Example 184 using N-(3-chloro-4-fluorophenyl)-2-(2-hydroxyethyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide and N-methyl-1-phenylmethanamine. C23H22ClFN6O. 454.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 11.07 (s, 1H), 8.90 (s, 1H), 8.30 (d, J = 5.0 Hz, 1H), 7.56 (dd, J = 6.4, 3.3 Hz, 2H), 7.50 (dt, J = 4.5, 2.9 Hz, 3H), 7.15 (d, J = 5.1 Hz, 1H), 7.03 (t, J = 9.1 Hz, 1H), 6.91 (dd, J = 6.5, 2.7 Hz, 1H), 6.51 (ddd, J = 8.9, 4.0, 2.7 Hz, 1H), 4.44 (s, 2H), 3.57 (t, J = 7.5 Hz, 2H), 3.36 (t, J = 7.4 Hz, 2H), 2.76 (s, 3H).
    • Example 397: N-(3-chloro-4-fluorophenyl)-2-((2-((2-ethylbutyl)(methyl)amino)ethyl)amino)-4,5-difluoro-N-hydroxy-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0774
  • Example 397 was made analogously to Example 395 using 2-ethylbutanal for the reductive amination. C23H28ClF3N6O. 498.1 (M+1).
    • Example 398: N-(3-chloro-4-fluorophenyl)-2-((2-((cyclopropylmethyl)(methyl)amino)ethyl)amino)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0775
  • Example 398 was made analogously to Example 394 using cyclopropanecarbaldehyde for the reductive amination. C21H22CIF3N6O. 468.1 (M+1). 1H NMR (400 MHz, Methanol-d4) δ 6.95 (t, J = 8.9 Hz, 1H), 6.92 - 6.86 (m, 2H), 6.66 (ddd, J = 8.9, 3.9, 2.8 Hz, 1H), 3.77 (t, J = 5.3 Hz, 2H), 3.46 (d, J = 8.4 Hz, 2H), 3.14 (d, J = 7.2 Hz, 2H), 3.02 (s, 3H), 1.16 (ddd, J = 7.7, 4.7, 2.9 Hz, 1H), 0.71 (dd, J = 8.1, 1.5 Hz, 2H), 0.40 (dd, J = 4.7, 1.3 Hz, 2H).
    • Example 399: N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(2-(methyl((tetrahydro-2H-pyran-4-yl)methyl)amino)ethyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0776
  • Example 399 was made analogously to Example 184 using N-methyl-1-(tetrahydro-2H-pyran-4-yl)methanamine. C22H26ClFN6O2. 461.9 (M+1).
    • Example 400: 2-(2-(((1,4-dioxan-2-yl)methyl)(methyl)amino)ethyl)-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0777
  • Example 400 was made analogously to Example 184 using 1-(1,4-dioxan-2-yl)-N-methylmethanamine hydrochloride. C21H24ClFN6O3. 463.9 (M+1). 1HNMR (400 MHz, DMSO-d6) δ 11.09 (s, 1H), 8.89 (s, 1H), 8.31 (d, J = 5.1 Hz, 1H), 7.16 (d, J = 5.1 Hz, 1H), 7.05 (t, J = 9.1 Hz, 1H), 6.93 (dd, J = 6.5, 2.7 Hz, 1H), 6.52 (ddd, J = 9.0, 4.0, 2.7 Hz, 1H), 4.10 - 4.01 (m, 1H), 3.83 - 3.20 (m, 13H), 2.89 (s, 3H).
    • Example 401: N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(2-(methyl(2-(tetrahydro-2H-pyran-4-yl)ethyl)amino)ethyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0778
  • Example 401 was made analogously to Example 184 using N-methyl-2-(tetrahydro-2H-pyran-4-yl)ethan-1-amine. C23H28ClFN6O2. 476.0 (M+1). 1HNMR (400 MHz, DMSO-d6) δ 11.07 (s, 1H), 8.91 (s, 1H), 8.30 (d, J = 5.1 Hz, 1H), 7.16 (d, J = 5.1 Hz, 1H), 7.04 (t, J = 9.1 Hz, 1H), 6.93 (dd, J = 6.5, 2.7 Hz, 1H), 6.55 - 6.48 (m, 1H), 3.83 (dd, J = 11.2, 4.3 Hz, 2H), 3.55 (s, 1H), 3.35 - 3.23 (m, 4H), 3.23 - 3.15 (m, 2H), 2.84 (s, 3H), 1.59 (dd, J = 15.6, 10.5 Hz, 6H), 1.20 (d, J = 11.8 Hz, 2H).
    • Example 402: N-(3-chloro-4-fluorophenyl)-2-((2-(cyclopropylamino)ethyl)amino)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0779
  • Example 402 was made analogously to Example 395 using 3-(2-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one in place of 3-(2-chloro-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one and tert-butyl (2-aminoethyl)(cyclopropyl)carbamate. C18H19ClFN7O. 404.8 (M+1). 1HNMR (400 MHz, DMSO-d6) δ 11.39 (s, 1H), 8.97 (s, 3H), 7.99 (d, J = 6.3 Hz, 1H), 7.11 (t, J = 9.1 Hz, 1H), 7.01 (dd, J = 6.5, 2.7 Hz, 1H), 6.95 (d, J = 6.3 Hz, 1H), 6.58 (ddd, J = 9.0, 4.1, 2.8 Hz, 1H), 3.75 (s, 2H), 3.31 (s, 2H), 2.80 (s, 1H), 0.87 - 0.75 (m, 4H).
    • Example 403: N-(3-chloro-4-fluorophenyl)-2-((2-(cyclopropyl(ethyl)amino)ethyl)amino)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0780
  • Example 403 was made analogously to Example 402 using N1-cyclopropyl-N1-ethylethane-1,2-diamine. C20H23ClFN7O. 432.2 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 8.95 (s, 1H), 7.97 (d, J = 6.1 Hz, 1H), 7.10 (t, J = 9.1 Hz, 1H), 6.99 (s, 1H), 6.93 (d, J = 6.0 Hz, 1H), 6.61 - 6.53 (m, 1H), 3.80 (s, 2H), 3.45 (s, 2H), 3.33 (s, 2H), 2.86 (s, 1H), 1.27 (t, J = 7.2 Hz, 3H), 1.00 - 0.78 (m, 4H).
    • Example 404: N-(2-((7-(N-(3-chloro-4-fluorophenyl)-N'-hydroxycarbamimidoyl)-1H-imidazo[4,5-b]pyridin-2-yl)amino)ethyl)acetamide
  • Figure imgb0781
  • Example 404 was made analogously to Example 402 using N-(2-aminoethyl)acetamide. C17H17ClFN7O2. 406.3 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 11.42 (s, 1H), 8.97 (s, 1H), 8.03 (s, 1H), 7.97 (d, J = 6.3 Hz, 1H), 7.11 (t, J = 9.0 Hz, 1H), 7.04 (dd, J = 6.5, 2.7 Hz, 1H), 6.92 (d, J = 6.3 Hz, 1H), 6.63 - 6.55 (m, 1H), 3.50 (d, J = 6.0 Hz, 2H), 3.30 (d, J = 6.0 Hz, 2H), 1.82 (s, 3H).
    • Example 405: N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((2-(methylsulfonamido)ethyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0782
  • Example 405 was made analogously to Example 402 using N-(2-aminoethyl)methanesulfonamide. C16H17ClFN7O3S. 442.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 11.44 (s, 1H), 8.97 (s, 1H), 7.97 (d, J = 6.3 Hz, 1H), 7.25 (d, J = 5.8 Hz, 1H), 7.11 (t, J = 9.0 Hz, 1H), 7.03 (s, 1H), 6.92 (d, J = 6.4 Hz, 1H), 6.59 (dt, J = 8.9, 3.4 Hz, 1H), 3.57 (d, J = 6.2 Hz, 2H), 3.21 (d, J = 6.1 Hz, 2H), 2.94 (s, 3H).
    • Example 406: N-(3-chloro-4-fluorophenyl)-2-((2-(cyclopropyl(isopropyl)amino)ethyl)amino)-N'-hydroay-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0783
  • Example 406 was made analogously to Example 402 using N1-cyclopropyl-N1-isopropylethane-1,2-diamine. C21H25ClFN7O. 446.4 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 11.30 (s, 1H), 8.94 (s, 1H), 7.97 (s, 1H), 7.10 (t, J = 9.0 Hz, 1H), 7.03 - 6.94 (m, 1H), 6.92 (d, J = 6.0 Hz, 1H), 6.56 (d, J = 8.4 Hz, 1H), 3.80 (s, 3H), 3.42 (s, 2H), 2.86 (s, 1H), 1.30 (d, J = 6.7 Hz, 6H), 1.01 (s, 2H), 0.89 (s, 2H).
    • Example 407: N-(3-chloro-4-fluorophenyl)-2-((2-(cyclopropyl(2-hydroxyethyl)amino)ethyl)amino)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0784
  • Example 407 was made analogously to Example 402 using 2-((2-aminoethyl)(cyclopropyl)amino)ethan-1-ol dihydrochloride and Hunig's base. C20H23ClFN7O2. 448.2 (M+1). 1H NMR (400 MHz, Methanol-d4) δ 7.89 (d, J = 6.5 Hz, 1H), 7.05 (d, J = 6.5 Hz, 1H), 7.03 - 6.95 (m, 2H), 6.67 (ddd, J = 8.9, 4.0, 2.8 Hz, 1H), 4.06 (t, J = 6.3 Hz, 2H), 4.01 - 3.95 (m, 2H), 3.71 (t, J = 6.3 Hz, 2H), 3.59 - 3.52 (m, 2H), 2.98 (dt, J = 7.3, 3.5 Hz, 1H), 1.19 - 1.12 (m, 2H), 1.07 - 1.01 (m, 2H).
    • Example 408: 2-((2-aminoethyl)amino)-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0785
  • Example 408 was made analogously to Example 402 using tert-butyl (2-aminoethyl)carbamate. C15H15ClFN7O. 364.9 (M+1).
    • Example 409: N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(((5-oxopyrrolidin-3-yl)methyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0786
  • Example 409 was made analogously to Example 402 using 4-(aminomethyl)pyrrolidin-2-one. C18H17ClFN7O2. 418.4 (M+1).
    • Example 410: 2-(((1H-pyrazol-5-yl)methyl)amino)-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0787
  • Example 410 was made analogously to Example 402 using (1H-pyrazol-5-yl)methanamine. C17H14ClFN8O. 401.1 (M+1).
    • Examples 411 and 412: N-(3-((7-(N-(3-chloro-4-fluorophenyl)-N'-hydroxycarbamimidoyl)-1H-imidazo[4,5-b]pyridin-2-yl)amino)propyl)acetamide and 2-((3-aminopropyl)amino)-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0788
  • 3-(2-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one (0.06 g, 0.121 mmol) and tert-butyl (3-aminopropyl)carbamate (0.181 mmol) were dissolved in DMSO (2.80 mL) and heated overnight at 60 C. The reaction was cooled to rt, diluted with water (3 mL) and extracted with EtOAc (3 x 2mL). Combined organic layers were washed with water (1 x 5 mL) and concentrated. The crude was dissolved in DCM (2 mL) and TFA (1.0 mL) was added and the reaction was allowed to stir at rt for 2 hours before being concentrated to dryness to give 3-(2-((3-aminopropyl)amino)-1H-imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one.
    Figure imgb0789
  • 3-(2-((3-aminopropyl)amino)-1H-imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one (0.015 g, 0.0317 mmol) was dissolved in THF (1.0 mL) and triethylamine (0.186 mmol) was added. Acetyl chloride (0.0557 mmol) was added slowly and the reaction was allowed to stir at rt for 1 hour before being concentrated to dryness. The residue was dissolved in THF (0.4 mL), MeOH (0.4 mL) and 1M NaOH (0.6 mL) and stirred at rt for 1 hour. The reaction was concentrated and purified by RP HPLC to give two products: N-(3-((7-(N-(3-chloro-4-fluorophenyl)-N'-hydroxycarbamimidoyl)-1H-imidazo[4,5-b]pyridin-2-yl)amino)propyl)acetamide (2.8 mg, 18%) and 2-((3-aminopropyl)amino)-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide.
  • N-(3-((7-(N-(3-chloro-4-fluorophenyl)-N'-hydroxycarbamimidoyl)-1H-imidazo[4,5-b]pyridin-2-yl)amino)propyl)acetamide: C18H19ClFN7O2. 420.2 (M+1). 1H NMR (400 MHz, Methanol-d4) δ 7.84 (d, J = 6.5 Hz, 1H), 7.04 - 6.96 (m, 3H), 6.67 (ddd, J = 8.9, 4.0, 2.8 Hz, 1H), 3.58 (t, J = 6.7 Hz, 2H), 3.28 (d, J = 6.7 Hz, 2H), 1.96 (s, 3H), 1.87 (t, J = 6.7 Hz, 2H).
  • 2-((3-aminopropyl)amino)-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide: C16H17ClFN7O. 378.3 (M+1). 1HNMR (400 MHz, Methanol-d4) δ 7.85 (d, J = 6.6 Hz, 1H), 7.04 - 6.95 (m, 3H), 6.68 (ddd, J = 8.9, 3.9, 2.8 Hz, 1H), 3.68 (t, J = 6.6 Hz, 2H), 3.11 - 3.03 (m, 2H), 2.12 - 2.02 (m, 2H).
    • Example 413: N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((2-(sulfamoylamino)ethyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0790
  • Example 413 was made analogously to Example 411 using 3-(2-((2-aminoethyl)amino)-1H-imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one, sulfamide, and pyridine. C15H16ClFN8O3S. 443.1 (M+1). 1H NMR (400 MHz, Methanol-d4) δ 7.84 (d, J = 6.5 Hz, 1H), 7.04 - 6.95 (m, 3H), 6.67 (ddd, J = 8.8, 4.0, 2.7 Hz, 1H), 3.73 (td, J = 6.1, 5.6, 0.9 Hz, 3H), 1.87 (ddt, J = 6.6, 4.6, 2.4 Hz, 1H).
    • Example 414: N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((2-(phenylsulfonamido)ethyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0791
  • Example 414 was made analogously to Example 411 using 3-(2-((2-aminoethyl)amino)-1H-imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one, benzenesulfonyl chloride, and triethylamine. C21H19ClFN7O3S. 504.1 (M+1).
    • Example 415: Methyl (2-((7-(N-(3-chloro-4-fluorophenyl)-N'-hydroxycarbamimidoyl)-1H-imidazo[4,5-b]pyridin-2-yl)amino)ethyl)carbamate
  • Figure imgb0792
  • Example 415 was made analogously to Example 411 using 3-(2-((2-aminoethyl)amino)-1H-imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one, methyl chloroformate, and triethylamine. C17H17ClFN7O3. 422.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 11.43 (s, 1H), 8.96 (s, 1H), 7.97 (d, J = 6.4 Hz, 1H), 7.28 (s, 1H), 7.11 (t, J = 9.0 Hz, 1H), 7.04 (dd, J = 6.5, 2.8 Hz, 1H), 6.93 (d, J = 6.3 Hz, 1H), 6.59 (ddd, J = 9.0, 4.0, 2.7 Hz, 1H), 3.53 (d, J = 3.9 Hz, 5H), 3.25 (d, J = 6.0 Hz, 2H).
    • Example 416: N-(3-chloro-4-fluorophenyl)-2-((2-(cyclopropanesulfonamido)ethyl)amino)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0793
  • Example 416 was made analogously to Example 411 using 3-(2-((2-aminoethyl)amino)-1H-imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one, cyclopropanesulfonyl chloride, and triethylamine. C18H19ClFN7O3S. 468.9 (M+1). 1H NMR (400 MHz, Methanol-d4) δ 7.84 (d, J = 6.5 Hz, 1H), 7.04 - 6.96 (m, 3H), 6.67 (ddd, J = 8.9, 3.9, 2.8 Hz, 1H), 3.70 (dd, J = 6.5, 5.3 Hz, 2H), 3.42 (dd, J = 6.6, 5.3 Hz, 2H), 2.56 (ddd, J = 7.9, 5.5, 2.9 Hz, 1H), 1.10 - 0.97 (m, 4H).
    • Example 417: N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((2-((trifluoromethyl)sulfonamido)ethyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0794
  • Example 417 was made analogously to Example 411 using 3-(2-((2-aminoethyl)amino)-1H-imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one, trifluoromethanesulfonyl chloride, and triethylamine. C16H14ClF4N7O3S. 496.3 (M+1).
    • Example 418: 2-(((1H-imidazol-2-yl)methyl)amino)-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0795
  • Example 418 was made analogously to Example 402 using (1H-imidazol-2-yl)methanamine dihydrochloride and Hunig's base. C17H14ClFN8O. 401.2 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 8.90 (s, 1H), 7.97 (d, J = 5.9 Hz, 1H), 7.60 (s, 2H), 7.10 (t, J = 9.0 Hz, 1H), 6.94 (d, J = 15.7 Hz, 2H), 6.60 - 6.53 (m, 1H), 4.92 (s, 2H).
    • Example 419: 2-(((1H-imidazol-5-yl)methyl)amino)-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0796
  • Example 419 was made analogously to Example 402 using (1H-imidazol-5-yl)methanamine dihydrochloride and Hunig's base. C17H14ClFN8O. 401.2 (M+1).
    • Example 420: N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(((3-methyl-1,2,4-oxadiazol-5-yl)methyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0797
  • Example 420 was made analogously to Example 402 using (3-methyl-1,2,4-oxadiazol-5-yl)methanamine. C17H14ClFN8O2. 417.2 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 8.97 (s, 1H), 8.50 (d, J = 12.2 Hz, 1H), 7.99 (d, J = 6.4 Hz, 1H), 7.11 (d, J = 9.1 Hz, 1H), 7.08 - 7.03 (m, 1H), 6.96 (d, J = 6.4 Hz, 1H), 6.60 (ddd, J = 9.0, 4.0, 2.7 Hz, 1H), 4.97 (d, J = 6.0 Hz, 2H), 2.32 (s, 3H).
    • Example 421: N-(3-bromophenyl)-N'-hydroxy-2-(methylamino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0798
  • Example 421 was made analogously to Example 402 using 4-(3-bromophenyl)-3-(2-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-7-yl)-1,2,4-oxadiazol-5(4H)-one and methylamine (2.0 M in MeOH). C14H13BrN6O. 361.2 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 8.97 (s, 1H), 7.97 (d, J = 6.2 Hz, 1H), 7.07 (d, J = 2.0 Hz, 1H), 7.02 - 6.92 (m, 3H), 6.57 (dt, J = 7.0, 2.1 Hz, 1H), 3.02 (d, J = 4.7 Hz, 3H).
    • Example 422: Methyl (3-((7-(N-(3-chloro-4-fluorophenyl)-N'-hydroxycarbamimidoyl)-1H-imidazo[4,5-b]pyridin-2-yl)amino)propyl)carbamate
  • Figure imgb0799
  • Example 422 was made analogously to Example 411 using 3-(2-((3-aminopropyl)amino)-1H-imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one, methyl chloroformate, and triethylamine. C18H19ClFN7O3. 436.2 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 8.94 (s, 1H), 7.96 (d, J = 6.2 Hz, 1H), 7.19 (d, J = 5.6 Hz, 1H), 7.10 (t, J = 9.0 Hz, 1H), 7.04 (dd, J = 6.6, 2.7 Hz, 1H), 6.91 (d, J = 6.2 Hz, 1H), 6.59 (ddd, J = 8.9, 4.0, 2.8 Hz, 1H), 3.53 (s, 3H), 3.44 (d, J = 6.5 Hz, 2H), 3.07 (d, J = 6.3 Hz, 2H), 1.79 - 1.64 (m, 2H).
    • Example 423: N-(3-bromophenyl)-N'-hydroxy-2-methoxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0800
  • Example 423 was made analogously to Example 402 using 4-(3-bromophenyl)-3-(2-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-7-yl)-1,2,4-oxadiazol-5(4H)-one and sodium hydride in MeOH to generate sodium methoxide in situ. C14H12BrN5O2. 362.0 (M+1).
    • Example 424: N-(3-bromophenyl)-N'-hydroxy-2-((2-(methylsulfonyl)ethyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0801
  • Example 424 was made analogously to Example 402 using 4-(3-bromophenyl)-3-(2-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-7-yl)-1,2,4-oxadiazol-5(4H)-one, 2-(methylsulfonyl)ethan-1-amine hydrochloride, and Hunig's base. C16H17BrN6O3S. 453.2 (M+1).
    • Example 425: N-(3-bromophenyl)-N'-hydroxy-2-((2-(methylsulfonamido)ethyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0802
  • Example 425 was made analogously to Example 424 using N-(2-aminoethyl)methanesulfonamide. C16H18BrN7O3S. 468.2 (M+1).
    • Example 426: N-(3-bromophenyl)-N'-hydroxy-2-((2-sulfamoylethyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0803
  • Example 426 was made analogously to Example 424 using 4-(3-bromophenyl)-3-(2-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-7-yl)-1,2,4-oxadiazol-5(4H)-one and 2-aminoethane-1-sulfonamide. C15H16BrN7O3S. 454.2 (M+1).
    • Example 427: N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(((5-methyl-1,3,4-oxadiazol-2-yl)methyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0804
  • Example 427 was made analogously to Example 402 using (5-methyl-1,3,4-oxadiazol-2-yl)methanamine oxalate and Hunig's base. C17H14ClFN8O2. 417.2 (M+1).
    • Example 428: N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-(((1-methylpiperidin-2-yl)methyl)amino)-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0805
  • Methyl 4,5-difluoro-2-(((1-methylpiperidin-2-yl)methyl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-7-carboxylate was made analogously to Example 39 using (1-methylpiperidin-2-yl)methanamine in place of N,N-dimethylpropane-1,3-diamine. The TFA salt of methyl 4,5-difluoro-2-(((1-methylpiperidin-2-yl)methyl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-7-carboxylate was isolated as a yellow oil. C22H34F2N4O3Si. 469.2 (M+1).
    Figure imgb0806
  • N-(3-chloro-4-fluorophenyl)-4,5-difluoro-2-(((1-methylpiperidin-2-yl)methyl)amino)-1H-benzo[d]imidazole-7-carboxamide was made analogously to Example 39 using methyl 4,5-difluoro-2-(((1-methylpiperidin-2-yl)methyl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-7-carboxylate in place of methyl 2-((3-(dimethylamino)propyl)amino)-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-7-carboxylate. The TFA salt of N-(3-chloro-4-fluorophenyl)-4,5-difluoro-2-(((1-methylpiperidin-2-yl)methyl)amino)-1H-benzo[d]imidazole-7-carboxamide was isolated as a white solid. C21H21ClF3N5O. 452.2/454.1 (M+1).
    Figure imgb0807
  • Example 428 was made analogously to Example 59 using N-(3-chloro-4-fluorophenyl)-4,5-difluoro-2-(((1-methylpiperidin-2-yl)methyl)amino)-1H-benzo[d]imidazole-7-carboxamide in place of N-(3-chloro-4-fluorophenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide. The TFA salt of N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-(((1-methylpiperidin-2-yl)methyl)amino)-1H-benzo[d]imidazole-7-carboximidamide was isolated as an off-white solid. C21H22ClF3N6O.467.2/469.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 10.78 (s, 1H), 9.25 (s, 1H), 8.69 (s, 1H), 7.10 (t, J = 9.1 Hz, 1H), 7.00 (s, 1H), 6.92 (dd, J = 6.5, 2.7 Hz, 1H), 6.83 (dd, J = 12.2, 6.8 Hz, 1H), 6.53 (ddd, J = 9.0, 4.1, 2.7 Hz, 1H), 3.79 (m, 1H), 3.68 (m, 1H), 3.41 (m, 1H), 3.24 (m, 1H), 3.04 (m, 1H), 2.97 (s, 3H), 2.83 (m, 1H), 1.94 (m, 1H), 1.85 - 1.70 (m, 2H), 1.65 - 1.40 (m, 2H).19F NMR (377 MHz, DMSO) δ -75.02 (9F), -127.46 (1F), -150.44 (1F), -157.01 (1F).
    • Example 429: N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-(((4-methylmorpholin-3-yl)methyl)amino)-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0808
  • Example 429 was made analogously to Example 39 using (4-methylmorpholin-3-yl)methanamine in place of N,N-dimethylpropane-1,3-diamine. The TFA salt of methyl 4,5-difluoro-2-(((4-methylmorpholin-3-yl)methyl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-7-carboxylate was isolated as a yellow oil. C21H32F2N4O4Si. 471.2 (M+1).
    Figure imgb0809
  • N-(3-chloro-4-fluorophenyl)-4,5-difluoro-2-(((4-methylmorpholin-3-yl)methyl)amino)-1H-benzo[d]imidazole-7-carboxamide was made analogously to Example 39 using methyl 4,5-difluoro-2-(((4-methylmorphohn-3-yl)methyl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-7-carboxylate in place of methyl 2-((3-(dimethylamino)propyl)amino)-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-7-carboxylate. The TFA salt of N-(3-chloro-4-fluorophenyl)-4,5-difluoro-2-(((4-methylmorpholin-3-yl)methyl)amino)-1H-benzo[d]imidazole-7-carboxamide was isolated as a white solid. C20H19ClF3N5O2. 454.2/456.1 (M+1).
    Figure imgb0810
  • Example 429 was made analogously to Example 59 using N-(3-chloro-4-fluorophenyl)-4,5-difluoro-2-(((4-methylmorpholin-3-yl)methyl)amino)-1H-benzo[d]imidazole-7-carboxamide in place of N-(3-chloro-4-fluorophenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide. The TFA salt of N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-(((4-methylmorpholin-3-yl)methyl)amino)-1H-benzo[d]imidazole-7-carboximidamide was isolated as an off-white solid. C20H20ClF3N6O2.469.1/471.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 10.76 (s, 1H), 8.68 (s, 1H), 7.09 (t, J = 9.1 Hz, 1H), 6.92 (dd, J = 6.5, 2.8 Hz, 2H), 6.83 (dd, J = 12.2, 6.8 Hz, 1H), 6.53 (ddd, J = 8.9, 4.0, 2.7 Hz, 1H), 4.10 - 3.84 (m, 4H), 3.80 - 3.65 (m, 2H), 3.58 - 3.34 (m, 2H), 3.26 (m, 1H), 3.03 (s, 3H). 19F NMR (377 MHz, DMSO-d6) δ - 74.98 (9F), -127.43 (1F), -150.47 (dd, J = 21.1, 12.8 Hz, 1F), -157.02 (1F).
    • Example 430: N-(3-bromophenyl)-2-((2-(dimethylamino)ethyl)amino)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0811
  • N-(3-bromophenyl)-2-((2-(dimethylamino)ethyl)amino)-4,5-difluoro-1H-benzo[d]imidazole-7-carboxamide was made analogously to Example 39 using methyl 2-((2-(dimethylamino)ethyl)amino)-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-7-carboxylate in place of methyl 2-((3-(dimethylamino)propyl)amino)-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-7-carboxylate. The TFA salt of N-(3-bromophenyl)-2-((2-(dimethylamino)ethyl)amino)-4,5-difluoro-1H-benzo[d]imidazole-7-carboxamide was isolated as a white solid. C18H18BrF2N5O. 438.1/440.1 (M+1).
    Figure imgb0812
  • Example 430 was made analogously to Example 59 using N-(3-bromophenyl)-2-((2-(dimethylamino)ethyl)amino)-4,5-difluoro-1H-benzo[d]imidazole-7-carboxamide in place of N-(3-chloro-4-fluorophenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide. The TFA salt of N-(3-bromophenyl)-2-((2-(dimethylamino)ethyl)amino)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide was isolated as an off-white solid. C18H19BrF2N6O.455.1/456.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 10.80 (s, 1H), 8.68 (s, 1H), 7.04 - 6.93 (m, 3H), 6.89 (s, 1H), 6.81 (dd, J = 12.2, 6.9 Hz, 1H), 6.54 (dt, J = 7.7, 1.7 Hz, 1H), 3.70 (m, 2H), 3.32 (m, 2H), 2.86 (s, 6H). 19F NMR (377 MHz, DMSO) δ -74.85 (9F), -150.52 (1F), -157.05 (1F).
    • Example 431: N-(3-chlorophenyl)-2-((2-(dimethylamino)ethyl)amino)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0813
  • N-(3-chlorophenyl)-2-((2-(dimethylamino)ethyl)amino)-4,5-difluoro-1H-benzo[d]imidazole-7-carboxamide was made analogously to Example 39 using methyl 2-((2-(dimethylamino)ethyl)amino)-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-7-carboxylate in place of methyl 2-((3-(dimethylamino)propyl)amino)-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-7-carboxylate. The TFA salt of N-(3-chlorophenyl)-2-((2-(dimethylamino)ethyl)amino)-4,5-difluoro-1H-benzo[d]imidazole-7-carboxamide was isolated as a white solid. C18H18ClF2N5O. 394.1/396.2 (M+1).
    Figure imgb0814
  • Example 431 was made analogously to Example 59 using N-(3-chlorophenyl)-2-((2-(dimethylamino)ethyl)amino)-4,5-difluoro-1H-benzo[d]imidazole-7-carboxamide in place of N-(3-chloro-4-fluorophenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide. The TFA salt of N-(3-chlorophenyl)-2-((2-(dimethylamino)ethyl)amino)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide was isolated as an off-white solid . C18H19ClF2N6O.409.1/411.1 (M+1)). 1H NMR (400 MHz, DMSO-d6) δ 10.79 (s, 1H), 8.68 (s, 1H), 7.05 (t, J = 8.0 Hz, 1H), 6.86 - 6.72 (m, 3H), 6.54 - 6.46 (m, 1H), 3.69 (s, 3H), 3.32 (s, 4H), 2.86 (s, 6H). 19F NMR (376 MHz, DMSO-d6) δ -74.52, - 150.61, -157.17.
    • Example 432: N-(3-bromo-4-fluorophenyl)-2-((2-(dimethylamino)ethyl)amino)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0815
  • N-(3-bromo-4-fluorophenyl)-2-((2-(dimethylamino)ethyl)amino)-4,5-difluoro-1H-benzo[d]imidazole-7-carboxamide was made analogously to Example 39 using methyl 2-((2-(dimethylamino)ethyl)amino)-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-7-carboxylate in place of methyl 2-((3-(dimethylamino)propyl)amino)-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-7-carboxylate and 3-bromo-4-fluoroaniline in place of 3-chloro-4-fluoroaniline. The TFA salt of N-(3-bromo-4-fluorophenyl)-2-((2-(dimethylamino)ethyl)amino)-4,5-difluoro-1H-benzo[d]imidazole-7-carboxamide was isolated as a white solid. C18H17BrF3N5O. 456.1/458.1 (M+1).
    Figure imgb0816
  • Example 432 was made analogously to Example 59 using N-(3-bromo-4-fluorophenyl)-2-((2-(dimethylamino)ethyl)amino)-4,5-difluoro-1H-benzo[d]imidazole-7-carboxamide in place of N-(3-chloro-4-fluorophenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide. The TFA salt of N-(3-bromo-4-fluorophenyl)-2-((2-(dimethylamino)ethyl)amino)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide was isolated as an off-white solid. C18H18BrF3N6O.471.2/474.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 10.71 (s, 1H), 8.64 (s, 1H), 7.08 - 7.01 (m, 2H), 6.79 (s, 2H), 6.54 (ddd, J = 9.0, 4.2, 2.7 Hz, 1H), 3.66 (s, 2H), 3.30 (s, 2H), 2.84 (s, 6H).
    • Example 433: N-(3-chloro-4-fluorophenyl)-4,5-difluoro-2-((3-morpholinopropyl)amino)-1H-benzo[d]imidazole-7-carboxamide
  • Figure imgb0817
  • Methyl 4,5-difluoro-2-((3-morpholinopropyl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-7-carboxylate was made analogously to Example 39 using 3-morpholinopropan-1-amine in place of N,N-dimethylpropane-1,3-diamine. The TFA salt of methyl 4,5-difluoro-2-((3-morpholinopropyl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-7-carboxylate was isolated as a yellow oil. C22H34F2N4O4Si. 485.1 (M+1).
    Figure imgb0818
  • N-(3-chloro-4-fluorophenyl)-4,5-difluoro-2-((3-morpholinopropyl)amino)-1H-benzo[d]imidazole-7-carboxamide was made analogously to Example 39 using methyl 4,5-difluoro-2-((3-morpholinopropyl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-7-carboxylate in place of methyl 2-((3-(dimethylamino)propyl)amino)-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-7-carboxylate. The TFA salt of N-(3-chloro-4-fluorophenyl)-4,5-difluoro-2-((3-morpholinopropyl)amino)-1H-benzo[d]imidazole-7-carboxamide was isolated as a white solid. C21H21ClF3N5O2. 468.2/470.1 (M+1).
    Figure imgb0819
  • Example 433 was made analogously to Example 432 using N-(3-chloro-4-fluorophenyl)-4,5-difluoro-2-((3-morpholinopropyl)amino)-1H-benzo[d]imidazole-7-carboxamide in place of N-(3-bromo-4-fluorophenyl)-2-((2-(dimethylamino)ethyl)amino)-4,5-difluoro-1H-benzo[d]imidazole-7-carboxamide. The TFA salt of N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((3-morpholinopropyl)amino)-1H-benzo[d]imidazole-7-carboximidamide was isolated as an off-white solid. C21H22ClF3N6O2.483.1/485.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 10.75 (s, 1H), 8.66 (s, 1H), 7.09 (t, J = 9.1 Hz, 1H), 6.92 (dd, J = 6.5, 2.7 Hz, 1H), 6.82 (s, 2H), 6.54 (dq, J = 9.0, 3.1 Hz, 1H), 3.82 (m, 2H), 3.42 (m, 2H), 3.27 (m, 2H), 3.17 (t, J = 7.9 Hz, 2H), 1.97 (t, J = 7.8 Hz, 2H).
    • Example 434: N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((3-(pyrrolidin-1-yl)propyl)amino)-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0820
  • Methyl 4,5-difluoro-2-((3-(pyrrolidin-1-yl)propyl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-7-carboxylate was made analogously to Example 39 using 3-(pyrrolidin-1-yl)propan-1-amine in place of N,N-dimethylpropane-1,3-diamine. The TFA salt of methyl 4,5-difluoro-2-((3-(pyrrolidin-1-yl)propyl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-7-carboxylate was isolated as a yellow oil. C22H34F2N4O3Si. 469.2 (M+1).
    Figure imgb0821
  • N-(3-chloro-4-fluorophenyl)-4,5-difluoro-2-((3-(pyrrolidin-1-yl)propyl)amino)-1H-benzo[d]imidazole-7-carboxamide was made analogously to Example 39 using methyl 4,5-difluoro-2-((3-(pyrrolidin-1-yl)propyl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-7-carboxylate in place of methyl 2-((3-(dimethylamino)propyl)amino)-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-7-carboxylate. The TFA salt of N-(3-chloro-4-fluorophenyl)-4,5-difluoro-2-((3-(pyrrolidin-1-yl)propyl)amino)-1H-benzo[d]imidazole-7-carboxamide was isolated as a white solid. C21H21ClF3N5O. 452.0/454.1 (M+1).
    Figure imgb0822
  • Example 434 was made analogously to Example 432 using N-(3-chloro-4-fluorophenyl)-4,5-difluoro-2-((3-(pyrrolidin-1-yl)propyl)amino)-1H-benzo[d]imidazole-7-carboxamide in place of N-(3-bromo-4-fluorophenyl)-2-((2-(dimethylamino)ethyl)amino)-4,5-difluoro-1H-benzo[d]imidazole-7-carboxamide. The TFA salt of N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((3-(pyrrolidin-1-yl)propyl)amino)-1H-benzo[d]imidazole-7-carboximidamide was isolated as an off-white solid. C21H22ClF3N6O.467.2/469.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 10.75 (s, 1H), 9.68 (s, 1H), 8.66 (s, 1H), 7.09 (t, J = 9.1 Hz, 1H), 6.92 (dd, J = 6.5, 2.7 Hz, 1H), 6.90-6.75 (m, 2H), 6.54 (ddd, J = 9.0, 4.1, 2.8 Hz, 1H), 3.55 - 3.34 (m, 8H), 3.17 (m, 2H), 1.93 (m, 6H). 19F NMR (377 MHz, DMSO) δ -74.57, -127.43, -150.48, - 157.56.
    • Example 435: 2-(((3R)-4-amino-1-methylpyrrolidin-3-yl)amino)-N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0823
  • Methyl (S)-4,5-difluoro-2-((1-methylpyrrolidin-3-yl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-7-carboxylate was made analogously to Example 39 using (S)-1-methylpyrrolidin-3-amine in place of N,N-dimethylpropane-1,3-diamine. The TFA salt of methyl (S)-4,5-difluoro-2-((1-methylpyrrolidin-3-yl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-7-carboxylate was isolated as a yellow oil. C21H32F2N4O3Si. 441.0 (M+1).
    Figure imgb0824
  • (S)-N-(3-chloro-4-fluorophenyl)-4,5-difluoro-2-((1-methylpyrrolidin-3-yl)amino)-1H-benzo[d]imidazole-7-carboxamide was made analogously to Example 39 using methyl (S)-4,5-difluoro-2-((1-methylpyrrolidin-3-yl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-7-carboxylate in place of methyl 2-((3-(dimethylamino)propyl)amino)-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-7-carboxylate. The TFA salt of (S)-N-(3-chloro-4-fluorophenyl)-4,5-difluoro-2-((1-methylpyrrolidin-3-yl)amino)-1H-benzo[d]imidazole-7-carboxamide was isolated as a white solid. C19H17ClF3N5O. 424.1/426.1 (M+1).
    Figure imgb0825
  • Example 435 was made analogously to Example 432 using (S)-N-(3-chloro-4-fluorophenyl)-4,5-difluoro-2-((1-methylpyrrolidin-3-yl)amino)-1H-benzo[d]imidazole-7-carboxamide in place of N-(3-bromo-4-fluorophenyl)-2-((2-(dimethylamino)ethyl)amino)-4,5-difluoro-1H-benzo[d]imidazole-7-carboxamide. The TFA salt of 2-(((3R)-4-amino-1-methylpyrrolidin-3-yl)amino)-N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide was isolated as an off-white solid (15.8 mg, 67%). C19H19ClF3N7O.454.1/456.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 10.80 (s, 1H), 8.67 (s, 1H), 7.10 (t, J = 9.2 Hz, 1H), 7.08 (br s, 1H), 6.92 (dd, J = 6.5, 2.7 Hz, 1H), 6.83 (dd, J = 12.2, 7.0 Hz, 1H), 6.54 (ddd, J = 8.9, 4.0, 2.7 Hz, 1H), 6.10 (s, 2H), 4.77 (s, 1H), 4.00 (dq, J = 8.3, 7.0 Hz, 1H), 3.90 (dd, J = 12.5, 8.1 Hz, 1H), 3.82 (t, J = 9.9 Hz, 1H), 3.67 (d, J = 12.7 Hz, 1H), 3.58 (td, J = 11.2, 8.1 Hz, 1H), 3.38 (s, 3H), 2.76 - 2.64 (m, 1H), 2.25 - 2.12 (m, 1H). 19F NMR (376 MHz, DMSO) δ -74.87, -127.5, -150.4, -156.9.
    • Example 436: N-(3-chloro-4-fluorophenyl)-2-((2-(dimethylamino)-2-phenylethyl)amino)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0826
  • Methyl 2-((2-(dimethylamino)-2-phenylethyl)amino)-4,5-difluoro-l-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-7-carboxylate was made analogously to Example 39 using N 1 ,N 1-dimethyl-1-phenylethane-1,2-diamine in place of N,N-dimethylpropane-1,3-diamine. The TFA salt of methyl 2-((2-(dimethylamino)-2-phenylethyl)amino)-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-7-carboxylate was isolated as a yellow oil. C25H34F2N4O3Si. 505.1 (M+1).
    Figure imgb0827
  • N-(3-chloro-4-fluorophenyl)-2-((2-(dimethylamino)-2-phenylethyl)amino)-4,5-difluoro-1H-benzo[d]imidazole-7-carboxamide was made analogously to Example 39 using methyl 2-((2-(dimethylamino)-2-phenylethyl)amino)-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-7-carboxylate in place of methyl 2-((3-(dimethylamino)propyl)amino)-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d|imidazole-7-carboxylate. The TFA salt of N-(3-chloro-4-fluorophenyl)-2-((2-(dimethylamino)-2-phenylethyl)amino)-4,5-difluoro-1H-benzo[d]imidazole-7-carboxamide was isolated as a white solid. C24H21ClF3N5O. 488.1/490.1 (M+1).
    Figure imgb0828
  • Example 436 was made analogously to Example 432 using N-(3-chloro-4-fluorophenyl)-2-((2-(dimethylamino)-2-phenylethyl)amino)-4,5-difluoro-1H-benzo[d]imidazole-7-carboxamide in place of N-(3-bromo-4-fluorophenyl)-2-((2-(dimethylamino)ethyl)amino)-4,5-difluoro-1H-benzo[d]imidazole-7-carboxamide. The TFA salt of N-(3-chloro-4-fluorophenyl)-2-((2-(dimethylamino)-2-phenylethyl)amino)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide was isolated as an off-white solid. C24H22ClF3N6O.503.1/505.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 10.75 (s, 1H), 10.68 (s, 1H), 8.66 (s, 1H), 7.62 - 7.55 (m, 1H), 7.53 (d, J = 3.3 Hz, 3H), 7.09 (t, J = 8.9 Hz, 1H), 6.89 (dd, J = 6.5, 2.7 Hz, 1H), 6.85 - 6.74 (m, 1H), 6.67 - 6.58 (m, 1H), 6.54 - 6.46 (m, 1H), 4.69 (m, 1H), 4.26 (m, 1H), 3.97 (m, 1H), 2.75 (s, 6H). 19F NMR (377 MHz, DMSO-d6) δ -74.37 (9F), -127.54 (1F), -150.55 (1F), -156.90 (1F).
    • Example 437: N-(3-chloro-4-fluorophenyl)-2-(((1R,2R)-2-(dimethylamino)cyclohexyl)amino)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0829
  • Methyl 2-(((1R,2R)-2-(dimethylamino)cyclohexyl)amino)-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-7-carboxylate was made analogously to Example 39 using (1R,2R)-N 1 ,N 1-dimethylcyclohexane-1,2-diamine in place of N,N-dimethylpropane-1,3-diamine. The TFA salt of methyl 2-(((1R,2R)-2-(dimethylamino)cyclohexyl)amino)-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-7-carboxylate was isolated as a yellow oil. C23H36F2N4O3Si. 483.2 (M+1).
    Figure imgb0830
  • N-(3-chloro-4-fluorophenyl)-2-(((1R,2R)-2-(dimethylamino)cyclohexyl)amino)-4,5-difluoro-1H-benzo[d]imidazole-7-carboxamide was made analogously to Example 39 using methyl 2-(((1R,2R)-2-(dimethylamino)cyclohexyl)amino)-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-7-carboxylate in place of methyl 2-((3-(dimethylamino)propyl)amino)-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-7-carboxylate. The TFA salt of N-(3-chloro-4-fluorophenyl)-2-(((1R,2R)-2-(dimethylamino)cyclohexyl)amino)-4,5-difluoro-1H-benzo[d]imidazole-7-carboxamide was isolated as a white solid. C22H23ClF3N5O. 466.2/468.1 (M+1).
    Figure imgb0831
  • Example 437 was made analogously to Example 402 using N-(3-chloro-4-fluorophenyl)-2-(((1R,2R)-2-(dimethylamino)cyclohexyl)amino)-4,5-difluoro-1H-benzo[d]imidazole-7-carboxamide in place of N-(3-chloro-4-fluorophenyl)-2-(((1-(dimethylamino)cyclohexyl)methyl)amino)-4,5-difluoro-1H-benzo[d]imidazole-7-carboxamide. The TFA salt of N-(3-chloro-4-fluorophenyl)-2-(((1R,2R)-2-(dimethylamino)cyclohexyl)amino)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide was isolated as an off-white solid. C22H24ClF3N6O.481.2/483.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 10.78 (s, 1H), 8.91 (s, 1H), 8.67 (s, 1H), 7.11 (t, J = 9.1 Hz, 1H), 6.91 (dd, J = 6.5, 2.7 Hz, 1H), 6.84 (dd, J = 12.3, 7.0 Hz, 1H), 6.79 (d, J = 9.7 Hz, 1H), 6.53 (ddd, J = 9.0, 4.0, 2.7 Hz, 1H), 4.02 (m, 1H), 3.33 (m, 1H), 2.77 (s, 3H), 2.78 (s, 3H), 2.07 (m, 1H), 1.93 (app. d, J = 9.9 Hz, 1H), 1.83 (app. d, J = 11.8 Hz, 1H), 1.70 (app. d, J = 9.5 Hz, 1H), 1.63 - 1.48 (m, 1H), 1.36 (dq, J = 27.4, 13.2, 12.3 Hz, 3H). 19F NMR (377 MHz, DMSO-d6) δ -75.02 (9F), -127.56 (1F), -150.41 (1F), -156.89 (1F).
    • Example 438: N-(3-chloro-4-fluorophenyl)-2-(((1-(dimethylamino)cyclopentyl)methyl)amino)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0832
  • Methyl 2-(((1-(dimethylamino)cyclopentyl)methyl)amino)-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-7-carboxylate was made analogously to Example 39 using 1-(aminomethyl)-N,N-dimethylcyclopentan-1-amine in place of N,N-dimethylpropane-1,3-diamine. The TFA salt of methyl 2-(((1-(dimethylamino)cyclopentyl)methyl)amino)-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-7-carboxylate was isolated as a yellow oil. C23H36F2N4O3Si 483.2 (M+1).
    Figure imgb0833
  • N-(3-chloro-4-fluorophenyl)-2-(((1-(dimethylamino)cyclopentyl)methyl)amino)-4,5-difluoro-1H-benzo[d]imidazole-7-carboxamide was made analogously to Example 39 using methyl 2-(((1-(dimethylamino)cyclopentyl)methyl)amino)-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-7-carboxylate in place of methyl 2-((3-(dimethylamino)propyl)amino)-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-7-carboxylate. The TFA salt of N-(3-chloro-4-fluorophenyl)-2-(((1-(dimethylamino)cyclopentyl)methyl)amino)-4,5-difluoro-1H-benzo[d]imidazole-7-carboxamide was isolated as a white solid. C22H23ClF3N5O. 466.2/468.1 (M+1).
    Figure imgb0834
  • Example 438 was made analogously to Example 402 using N-(3-chloro-4-fluorophenyl)-2-(((1-(dimethylamino)cyclopentyl)methyl)amino)-4,5-difluoro-1H-benzo[d]imidazole-7-carboxamide in place of N-(3-chloro-4-fluorophenyl)-2-(((1-(dimethylamino)cyclohexyl)methyl)amino)-4,5-difluoro-1H-benzo[d]imidazole-7-carboxamide. The TFA salt of N-(3-chloro-4-fluorophenyl)-2-(((1-(dimethylamino)cyclopentyl)methyl)amino)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide was isolated as an off-white solid. C22H24ClF3N6O.481.2/483.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 10.79 (s, 1H), 9.68 (s, 1H), 8.70 (s, 1H), 7.15 - 7.01 (m, 2H), 6.93 (dd, J = 6.5, 2.7 Hz, 1H), 6.85 (dd, J = 12.2, 6.9 Hz, 1H), 6.52 (ddd, J = 9.0, 4.1, 2.8 Hz, 1H), 3.74 (d, J = 6.6 Hz, 2H), 2.84 (s, 3H), 2.83 (s, 3H), 1.96 - 1.79 (m, 4H), 1.71 (t, J = 5.6 Hz, 4H). 19F NMR (377 MHz, DMSO) δ -74.89 (9F), -127.51 (1F), -150.42 (1F), -157.09 (1F).
    • Example 439: N-(3-chloro-4-fluorophenyl)-2-(((1S,3S)-3-(dimethylamino)cyclohexyl)amino)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0835
  • Methyl 2-((3-(dimethylamino)cyclohexyl)amino)-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-7-carboxylate was made analogously to Example 39 using N 1,N 1-dimethylcyclohexane-1,3-diamine in place of N,N-dimethylpropane-1,3-diamine. The TFA salt of methyl 2-((3-(dimethylamino)cyclohexyl)amino)-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-7-carboxylate was isolated as a yellow oil. C23H36F2N4O3Si 483.1 (M+1).
    Figure imgb0836
  • N-(3-chloro-4-fluorophenyl)-2-((3-(dimethylamino)cyclohexyl)amino)-4,5-difluoro-1H-benzo[d]imidazole-7-carboxamide was made analogously to Example 39 using methyl 2-((3-(dimethylamino)cyclohexyl)amino)-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-7-carboxylate in place of methyl 2-((3-(dimethylamino)propyl)amino)-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-7-carboxylate. The TFA salt of N-(3-chloro-4-fluorophenyl)-2-((3-(dimethylamino)cyclohexyl)amino)-4,5-difluoro-1H-benzo[d]imidazole-7-carboxamide was isolated as a white solid. C22H23ClF3N5O. 466.2 (M+1).
    Figure imgb0837
  • Example 439 was made analogously to Example 402 using N-(3-chloro-4-fluorophenyl)-2-((3-(dimethylamino)cyclohexyl)amino)-4,5-difluoro-1H-benzo[d]imidazole-7-carboxamide in place of N-(3-chloro-4-fluorophenyl)-2-(((1-(dimethylamino)cyclohexyl)methyl)amino)-4,5-difluoro-1H-benzo[d]imidazole-7-carboxamide. The two diastereomers were separated by reverse phase HPLC and the TFA salt of N-(3-chloro-4-fluorophenyl)-2-(((1S,3S)-3-(dimethylamino)cyclohexyl)amino)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide was isolated as an off-white solid. (C22H24ClF3N6O. 481.1/483.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 10.81 (s, 1H), 9.45 (s, 1H), 8.69 (s, 1H), 7.10 (t, J = 9.1 Hz, 1H), 6.92 (dd, J = 6.5, 2.7 Hz, 1H), 6.81 (t, J = 9.8 Hz, 1H), 6.54 (ddd, J = 9.0, 4.0, 2.7 Hz, 1H), 3.33 (m, 1H), 2.76 (d, J = 5.0 Hz, 3H), 2.74 (d, J = 4.9 Hz, 3H), 2.39 (d, J = 11.9 Hz, 1H), 1.93 (dd, J = 27.6, 11.7 Hz, 4H), 1.48 - 1.30 (m, 4H), 1.21 (d, J = 13.5 Hz, 1H). 19F NMR (377 MHz, DMSO-d6) δ -74.82, -127.48, -149.43, -156.88.
    • Example 440: N-(3-chloro-4-fluorophenyl)-2-(((1S,3R)-3-(dimethylamino)cyclohexyl)amino)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0838
  • The TFA salt of N-(3-chloro-4-fluorophenyl)-2-(((1S,3R)-3-(dimethylamino)cyclohexyl)amino)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide was isolated from the sequence described in Example 439 as an off-white solid. C22H24ClF3N6O. 481.1/483.0 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 10.77 (s, 1H), 9.27 (s, 1H), 8.65 (s, 1H), 7.11 (t, J = 9.1 Hz, 1H), 7.00 (s, 1H), 6.91 (dd, J = 6.5, 2.7 Hz, 1H), 6.79 (dd, J = 12.0, 7.5 Hz, 1H), 6.54 (dt, J = 9.1, 3.5 Hz, 1H), 5.06 (q, J = 9.0 Hz, 1H), 4.21 (m, 1H), 3.29 (m, 1H), 2.77 (d, J = 4.6 Hz, 3H), 2.72 (d, J = 4.7 Hz, 3H), 2.29 (d, J = 14.9 Hz, 1H), 1.98 (m, 1H), 1.77 (m, 3H), 1.56 (m, 3H).
    • Example 441: N-(3-chloro-4-fluorophenyl)-2-(((1-(dimethylamino)cyclobutyl)methyl)amino)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0839
  • Methyl 2-(((1-(dimethylamino)cyclobutyl)methyl)amino)-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-7-carboxylate was made analogously to Example 39 using 1-(aminomethyl)-N,N-dimethylcyclobutan-1-amine in place of N,N-dimethylpropane-1,3-diamine. The TFA salt of methyl 2-(((1-(dimethylamino)cyclobutyl)methyl)amino)-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-7-carboxylate was isolated as a yellow oil. C22H34F2N4O3Si. 469.2 (M+1).
    Figure imgb0840
  • N-(3-chloro-4-fluorophenyl)-2-(((1-(dimethylamino)cyclobutyl)methyl)amino)-4,5-difluoro-1H-benzo[d]imidazole-7-carboxamide was made analogously to Example 39 using methyl 2-(((1-(dimethylamino)cyclobutyl)methyl)amino)-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-7-carboxylate in place of methyl 2-((3-(dimethylamino)propyl)amino)-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-7-carboxylate. The TFA salt of N-(3-chloro-4-fluorophenyl)-2-(((1-(dimethylamino)cyclobutyl)methyl)amino)-4,5-difluoro-1H-benzo[d]imidazole-7-carboxamide was isolated as a white solid. C21H21ClF3N5O. 452.2/545.1 (M+1).
    Figure imgb0841
  • Example 441 was made analogously to Example 402 using N-(3-chloro-4-fluorophenyl)-2-(((1-(dimethylamino)cyclobutyl)methyl)amino)-4,5-difluoro-1H-benzo[d]imidazole-7-carboxamide in place of N-(3-chloro-4-fluorophenyl)-2-(((1-(dimethylamino)cyclohexyl)methyl)amino)-4,5-difluoro-1H-benzo[d]imidazole-7-carboxamide. The TFA salt of N-(3-chloro-4-fluorophenyl)-2-(((1-(dimethylamino)cyclobutyl)methyl)amino)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide was isolated as an off-white solid. C21H22ClF3N6O. 467.2/469.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 10.79 (s, 1H), 8.70 (s, 1H), 7.17 (t, J = 6.6 Hz, 1H), 7.08 (t, J = 9.1 Hz, 1H), 6.94 (dd, J = 6.5, 2.7 Hz, 1H), 6.87 (dd, J = 12.2, 6.9 Hz, 1H), 6.54 (ddd, J = 9.0, 4.0, 2.7 Hz, 1H), 6.06 (s, 1H), 4.06 (d, J = 6.6 Hz, 2H), 3.20 (s, 6H), 2.74 (dt, J = 14.1, 10.0 Hz, 2H), 2.12 - 1.99 (m, 2H), 1.85 - 1.70 (m, 2H). 19F NMR (376 MHz, DMSO-d6) δ -75.09, -127.43, -150.31, - 156.83.
    • Example 442: N-(3-chloro-4-fluorophenyl)-4,5-difluoro-7V-hydroxy-2-((1-methylpiperidin-4-yl)amino)-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0842
  • Methyl 4,5-difluoro-2-((1-methylpiperidin-4-yl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-7-carboxylate was made analogously to Example 39 using 1-methylpiperidin-4-amine in place of N,N-dimethylpropane-1,3-diamine. The TFA salt of methyl 4,5-difluoro-2-((1-methylpiperidin-4-yl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-7-carboxylate was isolated as a yellow oil. C21H32F2N4O3Si. 455.1 (M+1).
    Figure imgb0843
  • N-(3-chloro-4-fluorophenyl)-4,5-difluoro-2-((1-methylpiperidin-4-yl)amino)-1H-benzo[d]imidazole-7-carboxamide was made analogously to Example 39 using methyl 4,5-difluoro-2-((1-methylpiperidin-4-yl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-7-carboxylate in place of methyl 2-((3-(dimethylamino)propyl)amino)-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d|imidazole-7-carboxylate. The TFA salt of N-(3-chloro-4-fluorophenyl)-4,5-difluoro-2-((1-methylpiperidin-4-yl)amino)-1H-benzo[d]imidazole-7-carboxamide was isolated as a white solid. C20H19ClF3N5O. 438.2/440.3 (M+1).
    Figure imgb0844
  • Example 442 was made analogously to Example 402 using N-(3-chloro-4-fluorophenyl)-4,5-difluoro-2-((1-methylpiperidin-4-yl)amino)-1H-benzo[d]imidazole-7-carboxamide in place of N-(3-chloro-4-fluorophenyl)-2-(((1-(dimethylamino)cyclohexyl)methyl)amino)-4,5-difluoro-1H-benzo[d]imidazole-7-carboxamide. The TFA salt of N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((1-methylpiperidin-4-yl)amino)-1H-benzo[d]imidazole-7-carboximidamide was isolated as an off-white solid. C20H20ClF3N6O. 453.1/455.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 10.78 (s, 1H), 9.26 (s, 1H), 8.68 (s, 1H), 7.09 (t, J = 9.1 Hz, 1H), 6.92 (m, 1H), 6.82 (m, 1H), 6.53 (ddd, J = 8.9, 4.1, 2.7 Hz, 1H), 4.31 - 4.17 (m, 1H), 3.09 (q, J = 11.6 Hz, 4H), 2.80 (d, J = 4.7 Hz, 3H), 2.17 (d, J = 13.6 Hz, 2H), 1.64 (q, J = 13.0, 11.7 Hz, 2H).
    • Example 443: N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((1-methylpiperidin-3-yl)amino)-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0845
  • Methyl 4,5-difluoro-2-((1-methylpiperidin-3-yl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-7-carboxylate was made analogously to Example 39 using 1-methylpiperidin-3-amine in place of N,N-dimethylpropane-1,3-diamine. The TFA salt of methyl 4,5-difluoro-2-((1-methylpiperidin-3-yl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-7-carboxylate was isolated as a yellow oil. C21H32F2N4O3Si. 455.2 (M+1).
    Figure imgb0846
  • N-(3-chloro-4-fluorophenyl)-4,5-difluoro-2-((1-methylpiperidin-3-yl)amino)-1H-benzo[d]imidazole-7-carboxamide was made analogously to Example 39 using methyl 4,5-difluoro-2-((1-methylpiperidin-3-yl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-7-carboxylate in place of methyl 2-((3-(dimethylamino)propyl)amino)-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-7-carboxylate. The TFA salt of N-(3-chloro-4-fluorophenyl)-4,5-difluoro-2-((1-methylpiperidin-3-yl)amino)-1H-benzo[d]imidazole-7-carboxamide was isolated as a white solid. C20H19ClF3N5O. 438.2/440.1 (M+1).
    Figure imgb0847
  • Example 443 was made analogously to Example 402 using N-(3-chloro-4-fluorophenyl)-4,5-difluoro-2-((1-methylpiperidin-3-yl)amino)-1H-benzo[d]imidazole-7-carboxamide in place of N-(3-chloro-4-fluorophenyl)-2-(((1-(dimethylamino)cyclohexyl)methyl)amino)-4,5-difluoro-1H-benzo[d]imidazole-7-carboxamide. The TFA salt of N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((1-methylpiperidin-3-yl)amino)-1H-benzo[d]imidazole-7-carboximidamide was isolated as an off-white solid. C20H20ClF3N6O. 453.2/455.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 10.80 (s, 1H), 9.63 (s, 1H), 8.68 (s, 1H), 7.10 (t, J = 9.1 Hz, 1H), 6.92 (dd, J = 6.5, 2.8 Hz, 1H), 6.82 (dd, J = 12.3, 6.9 Hz, 1H), 6.54 (ddd, J = 9.0, 4.1, 2.7 Hz, 1H), 4.03 (m, 1H), 3.65 (m, 1H), 3.42 (m, 1H), 2.88 (d, J = 4.7 Hz, 1H), 2.83 (d, J = 4.6 Hz, 3H), 2.78 (d, J = 8.7 Hz, 1H), 2.06 - 1.65 (m, 3H), 1.53 - 1.38 (m, 1H). 19F NMR (377 MHz, DMSO-d6) δ -74.95 (9F), -127.50 (1F), -150.55 (1F), -156.90 (1F).
    • Example 444: N-(3-chloro-4-fluorophenyl)-2-(((1S,2S)-2-(dimethylamino)cyclohexyl)amino)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0848
  • Methyl 2-(((1S,2S)-2-(dimethylamino)cyclohexyl)amino)-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-7-carboxylate was made analogously to Example 39 using (1S,2S)-N1,N1-dimethylcyclohexane-1,2-diamine in place of N,N-dimethylpropane-1,3-diamine. The TFA salt of methyl 2-(((1S,2S)-2-(dimethylamino)cyclohexyl)amino)-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-7-carboxylate was isolated as a yellow oil. C23H36F2N4O3Si. 483.2/484.1 (M+1).
    Figure imgb0849
  • N-(3-chloro-4-fluorophenyl)-2-(((1S,2S)-2-(dimethylamino)cyclohexyl)amino)-4,5-difluoro-1H-benzo[d]imidazole-7-carboxamide was made analogously to Example 39 using methyl 2-(((1S,2S)-2-(dimethylamino)cyclohexyl)amino)-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-7-carboxylate in place of methyl 2-((3-(dimethylamino)propyl)amino)-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-7-carboxylate. The TFA salt of N-(3-chloro-4-fluorophenyl)-2-(((1S,2S)-2-(dimethylamino)cyclohexyl)amino)-4,5-difluoro-1H-benzo[d]imidazole-7-carboxamide was isolated as a white solid. C22H23ClF3N5O. 466.2/468.1 (M+1).
    Figure imgb0850
  • Example 444 was made analogously to Example 402 using N-(3-chloro-4-fluorophenyl)-2-(((1S,2S)-2-(dimethylamino)cyclohexyl)amino)-4,5-difluoro-1H-benzo[d]imidazole-7-carboxamide in place of N-(3-chloro-4-fluorophenyl)-2-(((1-(dimethylamino)cyclohexyl)methyl)amino)-4,5-difluoro-1H-benzo[d]imidazole-7-carboxamide. The TFA salt of N-(3-chloro-4-fluorophenyl)-2-(((1S,2S)-2-(dimethylamino)cyclohexyl)amino)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide was isolated as an off-white solid. C22H24ClF3N6O. 481.2/483.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 10.92 - 10.67 (m, 1H), 8.92 (s, 1H), 8.67 (s, 1H), 7.11 (t, J = 9.1 Hz, 1H), 6.91 (dd, J = 6.5, 2.7 Hz, 1H), 6.88 - 6.75 (m, 2H), 6.53 (ddd, J = 9.0, 4.0, 2.7 Hz, 1H), 4.04 (m, 1H), 3.33 (td, J = 11.6, 3.5 Hz, 1H), 2.77 (d, J = 4.3 Hz, 6H), 2.13 - 2.03 (m, 1H), 1.94 (app. d, J = 10.7 Hz, 1H), 1.83 (app. d, J = 11.9 Hz, 1H), 1.70 (app. d, J = 9.4 Hz, 1H), 1.53 (app. dd, J = 13.6, 10.1 Hz, 1H), 1.37 (m, 3H). 19F NMR (376 MHz, DMSO-d6) δ -75.01 (9F), -127.56 (1F), -150.41 (1F), -156.9 (d, J = 22.3 Hz, IF).
    • Example 445: (S)-N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-(piperidin-3-ylamino)-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0851
  • Example 445 was made analogously to Example 333 using tert-butyl (S)-3-aminopiperidine-1-carboxylate in place of tert-butyl (2-aminoethyl)carbamate. The TFA salt of (S)-N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-(piperidin-3-ylamino)-1H-benzo[d]imidazole-7-carboximidamide was isolated as an off-white solid. C19H18ClF3N6O. 439.2/441.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 10.78 (s, 1H), 8.69-8.50 (m, 3H), 7.10 (t, J = 9.1 Hz, 1H), 6.91 (dd, J = 6.5, 2.7 Hz, 1H), 6.86 (m, 1H), 6.79 (m, 1H), 6.55 (ddd, J = 9.0, 4.1, 2.8 Hz, 1H), 4.00 (m, 1H), 3.47 (app. d, J = 11.9 Hz, 1H), 3.21 (app. d, J = 12.3 Hz, 1H), 2.93 - 2.79 (m, 2H), 2.00 (m, 1H), 1.89 (m, 1H), 1.80 - 1.63 (m, 1H), 1.57 (m, 1H). 19F NMR (376 MHz, DMSO) δ -74.92, -127.48, - 150.57, -156.96.
    • Example 446: (R)-N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-(piperidin-3-ylamino)-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0852
  • Example 446 was made analogously to Example 333 using tert-butyl (R)-3-aminopiperidine-1-carboxylate in place of tert-butyl (2-aminoethyl)carbamate. The TFA salt of (R)-N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-(piperidin-3-ylamino)-1H-benzo[d]imidazole-7-carboximidamide was isolated as an off-white solid. C19H18ClF3N6O. 439.2/441.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 10.79 (s, 1H), 8.78 - 8.51 (m, 3H), 7.10 (t, J = 9.1 Hz, 1H), 6.91 (dd, J = 6.5, 2.7 Hz, 1H), 6.86 (d, J = 6.6 Hz, 1H), 6.81 (dd, J = 12.1, 6.8 Hz, 1H), 6.54 (ddd, J = 9.0, 4.0, 2.8 Hz, 1H), 4.02 (m, 1H), 3.47 (app. d, J = 12.2 Hz, 1H), 3.21 (app. d, J = 12.4 Hz, 1H), 2.93 - 2.80 (m, 2H), 2.00 (app. d, J = 12.2 Hz, 1H), 1.89 (m, 1H), 1.71 (m, 1H), 1.56 (m, 1H). 19F NMR (377 MHz, DMSO-d6) δ -74.88 (9F), -127.50 (1F), -150.58 (1F), -156.99 (1F).
    • Example 447: (S)-N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((1-methylpyrrolidin-3-yl)amino)-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0853
  • Example 447 was made analogously to Example 333 using (S)-1-methylpyrrolidin-3-amine in place of tert-butyl (2-aminoethyl)carbamate. The TFA salt of (S)-N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((1-methylpyrrolidin-3-yl)amino)-1H-benzo[d]imidazole-7-carboximidamide was isolated as an off-white solid. C19H18ClF3N6O.439.2/441.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 10.76 (br. s, 1H), 9.75 (br. s, 1H), 8.67 (d, J = 3.5 Hz, 1H), 7.09 (td, J = 9.1, 3.4 Hz, 1H), 6.98 (m, 1H), 6.92 (dt, J = 6.5, 2.4 Hz, 1H), 6.85 (m, 1H), 6.53 (dt, J = 8.9, 3.5 Hz, 1H), 4.49 (m, 1H), 3.94 (m, 1H), 3.36 (m, 1H), 3.23 (m, 1H), 3.06 (m, 1H), 2.89 (app. dd, J = 9.0, 4.8 Hz, 3H), 2.06 (m, 1H), 1.90 (m, 1H). 19F NMR (376 MHz, DMSO-d6) δ -74.77, -127.47, - 150.47, -156.78.
    • Example 448: N-(3-chloro-4-fluorophenyl)-2-((3-(dimethylamino)-2-hydroxypropyl)amino)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0854
  • Example 448 was made analogously to Example 333 using 1-amino-3-(dimethylamino)propan-2-ol in place of tert-butyl (2-aminoethyl)carbamate. The TFA salt of N-(3-chloro-4-fluorophenyl)-2-((3-(dimethylamino)-2-hydroxypropyl)amino)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide was isolated as an off-white solid. C19H20ClF3N6O2.457.2/459.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 10.86 (br. s, 1H), 9.38 (br. s, 1H), 8.73 (s, 1H), 7.30 (m, 1H), 7.10 (t, J = 9.1 Hz, 1H), 6.94 (dd, J = 6.5, 2.7 Hz, 1H), 6.88 (dd, J = 12.2, 6.9 Hz, 1H), 6.54 (ddd, J = 9.0, 4.0, 2.7 Hz, 1H), 4.11 (dq, J = 9.7, 5.0 Hz, 1H), 3.47 (dt, J = 13.9, 5.5 Hz, 1H), 3.39 (m, 1H), 3.16 (app. d, J = 12.8 Hz, 1H), 3.06 (dd, J = 12.9, 10.1 Hz, 1H), 2.81 (s, 6H). 19F NMR (377 MHz, DMSO-d6) δ -75.02, -127.32, -149.66, -156.59.
    • Example 449: N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((2-(4-methyl-3-oxopiperazin-1-yl)ethyl)amino)-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0855
  • Example 449 was made analogously to Example 333 using 4-(2-aminoethyl)-1-methylpiperazin-2-one in place of tert-butyl (2-aminoethyl)carbamate. The TFA salt of N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((2-(4-methyl-3-oxopiperazin-1-yl)ethyl)amino)-1H-benzo[d]imidazole-7-carboximidamide was isolated as an off-white solid. C21H21ClF3N7O2.496.2/498.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 10.81 (br. s, 1H), 8.71 (s, 1H), 7.14 (br. s, 1H), 7.10 (t, J = 9.1 Hz, 1H), 6.94 (dd, J = 6.5, 2.7 Hz, 1H), 6.87 (dd, J = 12.2, 6.9 Hz, 1H), 6.53 (ddd, J = 8.9, 4.0, 2.7 Hz, 1H), 3.90 (s, 2H), 3.71 (m, 2H), 3.65 - 3.50 (m, 4H), 3.35 (m, 2H), 2.89 (s, 3H). 19F NMR (376 MHz, DMSO-d6) δ -75.14, -127.23, -149.86, -156.94.
    • Example 450: N-(3-chloro-4-fluorophenyl)-2-(((1-(dimethylamino)cyclohexyl)methyl)amino)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0856
  • Methyl 4,5-difluoro-2-((1-methylpiperidin-3-yl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-7-carboxylate was made analogously to Example 39 using 1-(aminomethyl)-N,N-dimethylcyclohexan-1-amine in place of N,N-dimethylpropane-1,3-diamine. The TFA salt of methyl 2-(((1-(dimethylamino)cyclohexyl)methyl)amino)-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-7-carboxylate was isolated as a yellow oil. C21H32F2N4O3Si. 497.3 (M+1).
    Figure imgb0857
  • N-(3-chloro-4-fluorophenyl)-2-(((1-(dimethylamino)cyclohexyl)methyl)amino)-4,5-difluoro-1H-benzo[d]imidazole-7-carboxamide was made analogously to Example 39 using methyl 4,5-difluoro-2-((1-methylpiperidin-3-yl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-7-carboxylate in place of methyl 2-((3-(dimethylamino)propyl)amino)-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-7-carboxylate. N-(3-chloro-4-fluorophenyl)-2-(((1-(dimethylamino)cyclohexyl)methyl)amino)-4,5-difluoro-1H-benzo[d]imidazole-7-carboxamide was isolated as a white solid. C23H25ClF3N5O. 480.2/482.1 (M+1).
    Figure imgb0858
  • The TFA salt of N-(3-chloro-4-fluorophenyl)-2-(((1-(dimethylamino)cyclohexyl)methyl)amino)-4,5-difluoro-1H-benzo[d]imidazole-7-carboxamide (103 mg, 0.15 mmol, 1 equiv) was dissolved in EtOAc, saturated aqueous NaHCO3 was added and the mixture was extracted twice with EtOAc. The combined organics were dried over MgSO4, filtered and concentrated in vacuo. The resulting residue was dissolved in CH2Cl2 (1 mL) and potassium carbonate (148 mg, 01.05 mmol, 7 equiv) and PCl5 (95 mg, 0.46 mmol, 3 equiv) were added. The reaction was stirred at room temperature for 3 hours before being concentrated in vacuo. A solution of TMSONH2 (0.185 mL, 1.5 mmol, 10 equiv) in trifluoroethanol (1.5 mL) was added at 0 °C. The reaction was slowly warmed to room temperature and stirred for 1 hour before being concentrated in vacuo. A solution of 2N HCl was added and the resulting mixture was stirred for 30 minutes before diluting with DMF/H2O and purification by reverse phase HPLC. The TFA salt of N-(3-chloro-4-fluorophenyl)-2-(((1-(dimethylamino)cyclohexyl)methyl)amino)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide was isolated as an off-white solid. C23H26ClF3N6O.495.2/497.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 10.80 (s, 1H), 9.49 (br. s, 1H), 8.68 (s, 1H), 7.10 (t, J = 9.1 Hz, 1H), 7.03 (br. s, 1H), 6.92 (dd, J = 6.5, 2.7 Hz, 1H), 6.85 (dd, J = 12.2, 6.9 Hz, 1H), 6.53 (dt, J = 8.9, 3.5 Hz, 1H), 4.31 (m, 1H), 3.86 (d, J = 6.5 Hz, 1H), 2.81 (s, 3H), 2.80 (s, 3H), 1.83-1.93 (m, 2H), 1.74 - 1.43 (m, 7H), 1.20 (m, 1H). 19F NMR (376 MHz, DMSO) δ -75.00, -127.52, -150.3, -156.97.
    • Example 451: N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((1-methylazepan-3-yl)amino)-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0859
  • Example 451 was made analogously to Example 333 using 1-methylazepan-3-amine in place of tert-butyl (2-aminoethyl)carbamate. The TFA salt of N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((1-methylazepan-3-yl)amino)-1H-benzo[d]imidazole-7-carboximidamide was isolated as an off-white solid. C21H22ClF3N6O.467.2/469.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 10.77 (s, 1H), 9.68 (br. s, 1H), 8.66 (s, 1H), 7.10 (t, J = 9.1 Hz, 1H), 6.91 (dd, J = 6.5, 2.7 Hz, 1H), 6.83 (m, 1H), 6.54 (m, 1H), 4.19 (m, 1H), 3.37 (m, 2H), 3.20 (m, 2H), 2.87 (s, 3H), 2.03 (m, 1H), 1.97 - 1.54 (m, 5H). 19F NMR (376 MHz, DMSO-d6) δ -74.83, -127.52, -150.54, - 156.65.
    • Example 452: (S)-N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((2-(3-hydroxypyrrolidin-1-yl)ethyl)amino)-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0860
  • Example 452 was made analogously to Example 333 using (S)-1-(2-aminoethyl)pyrrolidin-3-ol in place of tert-butyl (2-aminoethyl)carbamate. The TFA salt of (S)-N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((2-(3-hydroxypyrrolidin-1-yl)ethyl)amino)-1H-benzo[d]imidazole-7-carboximidamide was isolated as an off-white solid. C20H20ClF3N6O2.469.2/471.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 10.76 (s, 1H), 10.04 (br. s, 1H), 8.68 (s, 1H), 7.09 (t, J = 9.1 Hz, 1H), 6.97-6.90 (m, 2H), 6.83 (dd, J = 12.2, 6.9 Hz, 1H), 6.53 (ddd, J = 9.0, 4.1, 2.8 Hz, 1H), 4.43 (m, 1H), 3.68 (m, 6H), 3.41 (m, 2H), 2.15 (m, 1H), 1.88 (m, 1H). 19F NMR (376 MHz, DMSO) δ - 74.97, -127.34, -150.40, -156.84.
    • Example 453: N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((1-(2-methoxyethyl)piperidin-3-yl)amino)-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0861
  • Example 453 was made analogously to Example 333 using 1-(2-methoxyethyl)piperidin-3-amine in place of tert-butyl (2-aminoethyl)carbamate. The TFA salt of N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((1-(2-methoxyethyl)piperidin-3-yl)amino)-1H-benzo[d]imidazole-7-carboximidamide was isolated as an off-white solid. C22H24ClF3N6O2.497.2/499.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 10.81 (s, 1H), 9.63 (br. s, 1H), 8.68 (s, 1H), 7.10 (t, J = 9.1 Hz, 1H), 6.96-6.88 (m, 2H), 6.81 (dd, J = 12.2, 6.9 Hz, 1H), 6.55 (ddd, J = 9.0, 4.0, 2.8 Hz, 1H), 3.72 (m, 1H), 3.67 (app. t, J = 4.9 Hz, 2H), 3.50 (m, 1H), 3.35 (m, 2H), 3.32 (s, 3H), 3.25 (m, 1H), 2.95-2.70 (m, 2H), 2.05-1.75 (m, 3H), 1.48 (m, 1H). 19F NMR (377 MHz, DMSO-d6) δ -75.0 (9F), -127.5 (1F), -150.6 (1F), -157.0 (1F).
    • Example 454: N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((1-(2-methoxyethyl)pyrrolidin-3-yl)amino)-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0862
  • Example 454 was made analogously to Example 333 using 1-(2-methoxyethyl)pyrrolidin-3-amine in place of tert-butyl (2-aminoethyl)carbamate. The TFA salt of N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((1-(2-methoxyethyl)pyrrolidin-3-yl)amino)-1H-benzo[d]imidazole-7-carboximidamide was isolated as an off-white solid. C21H22ClF3N6O2.483.3/485.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 10.80 (s, 1H), 10.19 (br. s, 1H), 8.72 (s, 1H), 7.26 (d, J = 10.0 Hz, 1H), 7.13 - 7.05 (m, 2H), 6.93 (dd, J = 6.5, 2.6 Hz, 1H), 6.87 (dt, J = 12.0, 4.8 Hz, 1H), 6.53 (ddd, J = 9.0, 4.0, 2.8 Hz, 1H), 4.65 - 4.45 (m, 1H), 3.98 - 3.70 (m, 1H), 3.67 - 3.56 (m, 3H), 3.50 - 3.37 (m, 3H), 3.32 (d, J = 7.0 Hz, 3H), 3.11 (m, 1H), 2.37 - 2.25 (m, 1H), 2.07 - 1.84 (m, 1H). 19F NMR (377 MHz, DMSO-d6) δ -75.04 (9F), -127.36 (1F), - 150.26 (1F), -156.63 (1F).
    • Example 455: N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((1-isopropylpiperidin-3-yl)amino)-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0863
  • Example 455 was made analogously to Example 333 using 1-isopropylpiperidin-3-amine in place of tert-butyl (2-aminoethyl)carbamate. The TFA salt of N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((1-isopropylpiperidin-3-yl)amino)-1H-benzo[d]imidazole-7-carboximidamide was isolated as an off-white solid. C22H24ClF3N6O.481.3/483.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 10.79 (s, 1H), 9.26 (s, 1H), 8.67 (s, 1H), 7.10 (t, J = 9.1 Hz, 1H), 6.92 (dd, J = 6.5, 2.7 Hz, 1H), 6.85 - 6.75 (m, 2H), 6.54 (m, 1H), 4.16 (m, 1H), 3.59 - 3.51 (m, 2H), 3.36 (m, 1H), 2.94 - 2.77 (m, 2H), 2.00 (m, 2H), 1.77 (m, 1H), 1.54 (m, 1H), 1.26 (t, J = 6.2 Hz, 6H). 19F NMR (377 MHz, DMSO-d6) δ -74.90 (9F), -127.52 (1F), -150.59 (1F), -157.02 (1F).
    • Example 456: N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((2-(3-methoxyazetidin-1-yl)ethyl)amino)-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0864
  • Example 456 was made analogously to Example 333 using 2-(3-methoxyazetidin-1-yl)ethan-1-amine in place of tert-butyl (2-aminoethyl)carbamate. The TFA salt of N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((2-(3-methoxyazetidin-1-yl)ethyl)amino)-1H-benzo[d]imidazole-7-carboximidamide was isolated as an off-white solid. C20H20ClF3N6O2.469.2/471.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 10.79 (s, 1H), 9.94 (br. s, 1H), 8.72 (s, 1H), 7.09 (t, J = 9.1 Hz, 1H), 6.97 - 6.90 (m, 2H), 6.85 (dd, J = 12.2, 6.9 Hz, 1H), 6.53 (ddd, J = 8.9, 4.0, 2.8 Hz, 1H), 4.30 - 4.15 (m, 3H), 4.03 (m, 2H), 3.55 (m, 2H), 3.41 (m, 2H), 3.25 (s, 3H). 19F NMR (377 MHz, DMSO-d6) δ -75.03 (9F), -127.30 (1F), -150.32 (1F), -157.00 (1F).
    • Example 457: (R)-N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((1-methylpyrrolidin-3-yl)amino)-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0865
  • Example 457 was made analogously to Example 333 using (R)-1-methylpyrrolidin-3-amine in place of tert-butyl (2-aminoethyl)carbamate. The TFA salt of (R)-N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((1-methylpyrrolidin-3-yl)amino)-1H-benzo[d]imidazole-7-carboximidamide was isolated as an off-white solid. C19H18ClF3N6O.439.2/441.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 10.80 (s, 1H), 10.11 (br. s, 0.5H), 9.85 (br. s, 0.5H), 8.71 (s, 1H), 7.28 (d, J = 9.3 Hz, 0.5H), 7.15 - 7.01 (m, 1.5H), 6.93 (dt, J = 6.3, 2.8 Hz, 1H), 6.87 (dd, J = 12.2, 6.9 Hz, 1H), 6.53 (m, 1H), 4.53 (m, 0.5H), 4.45 (m, 0.5H), 3.71 (m, 0.5H), 3.62 (m, 0.5H), 3.35 (m, 1H), 3.23 (m, 0.5H), 3.16 - 2.97 (m, 1.5H), 2.90 (d, J = 5.0 Hz, 1.5H), 2.88 (d, J = 4.6 Hz, 1.5H), 2.56 (m, 0.5H), 2.31 (m, 0.5H), 2.06 (m, 0.5H), 1.91 (m, 0.5H). 19F NMR (377 MHz, DMSO-d6) δ -75.00, -127.38, -150.33, -156.70.
    • Example 458: N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-(((3R,4R)-4-methoxy-1-methylpyrrolidin-3-yl)amino)-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0866
  • Example 458 was made analogously to Example 333 using (3R,4R)-4-methoxy-1-methylpyrrolidin-3-amine in place of tert-butyl (2-aminoethyl)carbamate. The TFA salt of N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-(((3R,4R)-4-methoxy-1-methylpyrrolidin-3-yl)amino)-1H-benzo[d]imidazole-7-carboximidamide was isolated as an off-white solid. C20H20ClF3N6O2.469.2/471.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 10.76 (s, 1H), 10.13 (br. s, 1H), 8.70 (s, 1H), 7.20 (m, 1H), 7.09 (td, J = 9.1, 3.0 Hz, 1H), 6.92 (dd, J = 6.5, 2.7 Hz, 1H), 6.86 (m, 1H), 6.53 (dt, J = 8.9, 3.4 Hz, 1H), 4.41 (m, 1H), 4.09 (m, 1H), 3.95 (m, 1H), 3.71 (m, 1H), 3.37 (m, 3H), 3.21 (m, 1H), 3.10 (m, 1H), 2.90 (m, 3H). 19F NMR (377 MHz, DMSO-d6) δ -74.80, -127.49, - 150.49, -157.01.
    • Example 459: (S)-N-(3-chlorophenyl)-4,5-difluoro-N'-hydroxy-2-((1-methylpiperidin-3-yl)amino)-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0867
  • Example 459 was made analogously to Example 460 using (S)-N-(3-chlorophenyl)-4,5-difluoro-2-((1-methylpiperidin-3-yl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-7-carboxylate. The TFA salt of (S*)-N-(3-chlorophenyl)-4,5-difluoro-N'-hydroxy-2-((1-methylpiperidin-3-yl)amino)-1H-benzo[d]imidazole-7-carboximidamide was isolated as an off-white solid. C20H21ClF2N6O.435.2/437.1 (M+1);435.2/437.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 10.90 (s, 1H), 9.66 (br. s, 1H), 8.67 (s, 1H), 7.06 (t, J = 8.1 Hz, 1H), 6.95 (m, 1H), 6.82 (dd, J = 8.0, 2.2 Hz, 1H), 6.79 (t, J = 2.2 Hz, 1H), 6.53 (dd, J = 8.2, 2.1 Hz, 1H), 4.06 (m, 1H), 3.67 (m, 1H), 3.42 (m, 1H), 2.83 (d, J = 4.4 Hz, 3H), 2.82 - 2.73 (m, 2H), 2.00 (m, 2H), 1.75 (m, 1H), 1.45 (m, 1H).; 1H NMR (400 MHz, DMSO-d6) δ 10.88 (s, 1H), 9.63 (br. s, 1H), 8.69 (s, 1H), 7.06 (t, J = 8.0 Hz, 1H), 6.92 (m, 1H), 6.83 (m, 2H), 6.79 (t, J = 2.2 Hz, 1H), 6.52 (dd, J = 8.1, 2.2 Hz, 1H), 4.06 (m, 1H), 3.65 (m, 1H), 3.42 (m, 1H), 2.83 (d, J = 4.6 Hz, 3H), 2.81 - 2.75 (m, 2H), 1.99 (m, 2H), 1.72 (m, 1H), 1.45 (m, 1H). 19F NMR (376 MHz, DMSO-d6) δ -74.95, -150.50, -156.86.
    • Example 460: (R)-N-(3-chlorophenyl)-4,5-difluoro-N'-hydroxy-2-((1-methylpiperidin-3-yl)amino)-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0868
  • Methyl 4,5-difluoro-2-((1-methylpiperidin-3-yl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-7-carboxylate was made analogously to Example 39 using 1-methylpiperidin-3-amine in place of N,N-dimethylpropane-1,3-diamine. The TFA salt of methyl 4,5-difluoro-2-((1-methylpiperidin-3-yl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-7-carboxylate was isolated as an amorphous yellow oil. C21H32F2N4O3Si. 455.2 (M+1).
    Figure imgb0869
  • N-(3-chlorophenyl)-4,5-difluoro-2-((1-methylpiperidin-3-yl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-7-carboxamide was made analogously to Example 39 using methyl 4,5-difluoro-2-((1-methylpiperidin-3-yl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-7-carboxylate in place of methyl 2-((3-(dimethylamino)propyl)amino)-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-7-carboxylate and 3-chloroaniline in place of 3-chloro-4-fluoroaniline. N-(3-chlorophenyl)-4,5-difluoro-2-((1-methylpiperidin-3-yl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-7- carboxamide was purified by silica gel chromatography (0-16% MeOH/CH2Cl2 w/ 0.5% NEt3) isolated as a white solid. C21H32F2N4O3Si. 455.2 (M+1). Each enantiomer was isolated using chiral SFC (AD-H, 15% iPrOH, 60 mL/min, 100 bar). C26H34ClF2N5O2Si. 550.3/552.1 (M+1).
    Figure imgb0870
  • (R)-N-(3-chlorophenyl)-4,5-difluoro-2-((1-methylpiperidin-3-yl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-7-carboxamide (60 mg, 0.11 mmol, 1 equiv) was dissolved in CH2Cl2 (2 mL) and TFA (2 mL) was added. The SEM-deprotection was stirred overnight before being concentrated in vacuo. The crude product was dissolved in EtOAc, saturated aqueous NaHCO3 was added and the mixture was extracted twice with EtOAc. The combined organics were dried over MgSO4, filtered and concentrated in vacuo. The resulting residue was dissolved in CH2Cl2 (1 mL) and potassium carbonate (106 mg, 0.76 mmol, 7 equiv) and PCl5 (68 mg, 0.33 mmol, 3 equiv) were added. The reaction was stirred at room temperature for 3 hours before being concentrated in vacuo. A solution of TMSONH2 (0.132 mL, 1.1 mmol, 10 equiv) in trifluoroethanol (1.5 mL) was added at 0 °C. The reaction was slowly warmed to room temperature and stirred for 1 hour before being concentrated in vacuo. A solution of 2N HCl was added and the resulting mixture was stirred for 30 minutes before diluting with DMF/H2O and purification by reverse phase HPLC. The TFA salt of (R)-N-(3-chlorophenyl)-4,5-difluoro-N'-hydroxy-2-((1-methylpiperidin-3-yl)amino)-1H-benzo[d]imidazole-7-carboximidamide was isolated as an off-white solid. C20H21ClF2N6O.435.2/437.1 (M+1);435.2/437.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 10.90 (s, 1H), 9.66 (br. s, 1H), 8.67 (s, 1H), 7.06 (t, J = 8.1 Hz, 1H), 6.95 (m, 1H), 6.82 (dd, J = 8.0, 2.2 Hz, 1H), 6.79 (t, J = 2.2 Hz, 1H), 6.53 (dd, J = 8.2, 2.1 Hz, 1H), 4.06 (m, 1H), 3.67 (m, 1H), 3.42 (m, 1H), 2.83 (d, J = 4.4 Hz, 3H), 2.82 - 2.73 (m, 2H), 2.00 (m, 2H), 1.75 (m, 1H), 1.45 (m, 1H).;1H NMR (400 MHz, DMSO-d6) δ 10.88 (s, 1H), 9.63 (br. s, 1H), 8.69 (s, 1H), 7.06 (t, J = 8.0 Hz, 1H), 6.92 (m, 1H), 6.83 (m, 2H), 6.79 (t, J = 2.2 Hz, 1H), 6.52 (dd, J = 8.1, 2.2 Hz, 1H), 4.06 (m, 1H), 3.65 (m, 1H), 3.42 (m, 1H), 2.83 (d, J = 4.6 Hz, 3H), 2.81 - 2.75 (m, 2H), 1.99 (m, 2H), 1.72 (m, 1H), 1.45 (m, 1H). 19F NMR (376 MHz, DMSO-d6) δ -74.95, -150.50, -156.86.
    • Example 461: N-(3-chloro-4-fluorophenyl)-2-((2-(dimethylamino)cyclopentyl)amino)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0871
  • Example 461 was made analogously to Example 333 using N 1,N 1-dimethylcyclopentane-1,2-diamine in place of tert-butyl (2-aminoethyl)carbamate. The TFA salt of N-(3-chloro-4-fluorophenyl)-2-((2-(dimethylamino)cyclopentyl)amino)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide was isolated as an off-white solid. C21H22ClF3N6O.467.3/469.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 10.74 (s, 1H), 8.69 (s, 1H), 7.09 (t, J = 9.0 Hz, 1H), 6.91 (dd, J = 6.5, 2.7 Hz, 1H), 6.83 (m, 1H), 6.52 (m, 1H), 4.34 (m, 1H), 3.63 (m, 1H), 2.85 (s, 6H), 2.15 - 2.00 (m, 2H), 1.87 (m, 1H), 1.79 - 1.63 (m, 3H).
    • Example 462: (S)-2-(azepan-3-ylamino)-N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0872
  • Example 462 was made analogously to Example 333 using tert-butyl (S)-3-aminoazepane-1-carboxylate in place of tert-butyl (2-aminoethyl)carbamate. The TFA salt of (S)-2-(azepan-3-ylamino)-N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide was isolated as an off-white solid. C20H20ClF3N6O.453.3 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 10.79 (s, 1H), 8.77 (br. s, 2H), 8.66 (s, 1H), 7.10 (t, J = 9.1 Hz, 1H), 6.91 (dd, J = 6.5, 2.7 Hz, 1H), 6.86 (d, J = 6.9 Hz, 1H), 6.82 (dd, J = 12.3, 6.9 Hz, 1H), 6.58 - 6.51 (m, 1H), 4.15 (m, 1H), 3.42 (m, 1H), 3.26 (m, 1H), 3.21 - 3.11 (m, 2H), 2.04 (m, 1H), 1.92 - 1.54 (m, 5H). 19F NMR (376 MHz, DMSO-d6) δ -74.9, -127.5, -150.5, -156.8.
    • Example 463: ( R)-2-(azepan-3-ylamino)-N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0873
  • Example 463 was made analogously to Example 333 using tert-butyl (R)-3-aminoazepane-1-carboxylate in place of tert-butyl (2-aminoethyl)carbamate. The TFA salt of (R)-2-(azepan-3-ylamino)-N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide was isolated as an off-white solid. C20H20ClF3N6O.453.2/455.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 10.78 (s, 1H), 8.76 (br. s, 2H), 8.66 (s, 1H), 7.10 (t, J = 9.1 Hz, 1H), 6.91 (dd, J = 6.5, 2.7 Hz, 1H), 6.83 (d, J = 6.8 Hz, 1H), 6.80 (d, J = 6.7 Hz, 1H), 6.54 (ddd, J = 9.0, 4.1, 2.8 Hz, 1H), 4.15 (m, 1H), 3.42 (m, 1H), 3.26 (m, 1H), 3.20 - 3.07 (m, 2H), 2.05 (m, 1H), 1.91 - 1.54 (m, 5H). 19F NMR (376 MHz, DMSO-d6) δ -74.8, -127.5, -150.5, -156.8.
    • Example 464: N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-(pyrrolidin-3-ylamino)-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0874
  • Example 464 was made analogously to Example 333 using tert-butyl 3-aminopyrrolidine-1-carboxylate in place of tert-butyl (2-aminoethyl)carbamate. The TFA salt of N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-(pyrrolidin-3-ylamino)-1H-benzo[d]imidazole-7-carboximidamide was isolated as an off-white solid. C18H16ClF3N6O.425.2/427.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 10.78 (s, 1H), 8.89 (br. s, 1H), 8.79 (br. s, 1H), 8.70 (s, 1H), 7.12 - 7.05 (m, 2H), 6.92 (dd, J = 6.5, 2.7 Hz, 1H), 6.85 (dd, J = 12.3, 6.9 Hz, 1H), 6.53 (ddd, J = 8.9, 4.0, 2.7 Hz, 1H), 4.44 (m, 1H), 3.47 (m, 1H), 3.27 (m, 2H), 2.27 (m, 1H), 1.94 (m, 1H). 19F NMR (377 MHz, DMSO-d6) δ -74.9 (9F), -127.4 (1F), -150.44 (1F), -156.81 (1F).
    • Example 465: (R)-N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((1-(oxetan-3-yl)piperidin-3-yl)amino)-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0875
  • Example 465 was made analogously to Example 333 using (R)-1-(oxetan-3-yl)piperidin-3-amine in place of tert-butyl (2-aminoethyl)carbamate. The TFA salt of (R)-N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((1-(oxetan-3-yl)piperidin-3-yl)amino)-1H-benzo[d]imidazole-7-carboximidamide was isolated as an off-white solid. C22H22ClF3N6O2.495.3/497.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 10.82 (s, 1H), 10.61 br. (s, 1H), 8.70 (s, 1H), 7.10 (t, J = 9.1 Hz, 1H), 7.04 (m, 1H), 6.92 (dd, J = 6.6, 2.7 Hz, 1H), 6.84 (dd, J = 12.3, 6.9 Hz, 1H), 6.54 (dt, J = 8.9, 3.4 Hz, 1H), 4.80 - 4.65 (m, 4H), 4.40 (m, 1H), 4.14 (m, 1H), 3.53 (m, 1H), 3.38 (m, 1H), 2.84 - 2.65 (m, 2H), 2.1 - 1.90 (m, 2H), 1.77 (m, 1H), 1.53 (m, 1H). 19F NMR (377 MHz, DMSO-d6) δ -74.8 (9F), -127.3 (1F), -150.3 (1F), -156.7 (1F).
    • Example 466: N-(3-chloro-4-fluorophenyl)-2-(((1,4-dimethylpiperidin-2-yl)methyl)amino)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0876
  • Example 466 was made analogously to Example 333 using (1,4-dimethylpiperidin-2-yl)methanamine in place of tert-butyl (2-aminoethyl)carbamate. The TFA salt of N-(3-chloro-4-fluorophenyl)-2-(((1,4-dimethylpiperidin-2-yl)methyl)amino)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide was isolated as an off-white solid. C22H24ClF3N6O.481.3/483.2 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 10.79 (s, 1H), 9.20 (br. s, 1H), 8.69 (s, 1H), 7.10 (t, J = 9.1 Hz, 1H), 7.02 (m, 1H), 6.92 (dd, J = 6.5, 2.7 Hz, 1H), 6.84 (dd, J = 12.2, 6.9 Hz, 1H), 6.54 (ddd, J = 9.0, 4.1, 2.7 Hz, 1H), 3.81 (m, 1H), 3.66 (m, 1H), 3.40 (m, 1H), 3.27 (m, 1H), 3.08 (m, 1H), 2.99 (s, 3H), 1.93 (m, 1H), 1.84 - 1.60 (m, 2H), 1.25 (m, 1H), 0.93 (d, J = 6.4 Hz, 3H). 19F NMR (376 MHz, DMSO-d6) δ -75.1 , -127.4 , -150.4, -157.0.
    • Example 467: N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((morpholin-3-ylmethyl)amino)-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0877
  • Example 467 was made analogously to Example 333 using tert-butyl 3-(aminomethyl)morpholine-4-carboxylate in place of tert-butyl (2-aminoethyl)carbamate. The TFA salt of N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((morpholin-3-ylmethyl)amino)-1H-benzo[d]imidazole-7-carboximidamide was isolated as an off-white solid. C19H18ClF3N6O2.455.2/457.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 10.80 (s, 1H), 9.06 (br. s, 2H), 8.71 (s, 1H), 7.10 (t, J = 9.1 Hz, 1H), 7.02 (m, 1H), 6.92 (dd, J = 6.6, 2.7 Hz, 1H), 6.83 (dd, J = 12.3, 6.9 Hz, 1H), 6.53 (dt, J = 9.0, 3.4 Hz, 1H), 3.95 (m, 1H), 3.88 (m, 1H), 3.67 (m, 1H), 3.62 - 3.50 (m, 4H), 3.30 (m, 1H), 3.09 (m, 1H). 19F NMR (377 MHz, DMSO-d6) δ -74.9 (9F), -127.2 (1F), -150.2 (1F), -156.4 (1F).
    • Example 468: N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-(((3R,4S)-4-hydroxypyrrolidin-3-yl)amino)-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0878
  • Example 468 was made analogously to Example 333 using tert-butyl (3R,4S)-3-amino-4-hydroxypyrrolidine-1-carboxylate in place of tert-butyl (2-aminoethyl)carbamate. The TFA salt of N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-(((3R,4S)-4-hydroxypyrrolidin-3-yl)amino)-1H-benzo[d]imidazole-7-carboximidamide was isolated as an off-white solid. C18H16ClF3N6O2.441.2/443.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 10.83 (s, 1H), 9.18 (br. s, 1H), 8.81 (br. s, 1H), 8.69 (s, 1H), 7.11 (t, J = 9.1 Hz, 1H), 6.95 - 6.90 (m, 2H), 6.82 (dd, J = 12.3, 6.8 Hz, 1H), 6.53 (dt, J = 8.8, 3.4 Hz, 1H), 6.13 (br. s, 1H), 4.49 (m, 1H), 4.36 (m, 1H), 3.56 (m, 1H), 3.42 (m, 1H), 3.17 (m, 1H), 3.01 (m, 1H). 19F NMR (377 MHz, DMSO-d6) δ -74.7 (9F), -127.4 (1F), -150.3 (1F), -156.8 (1F).
    • Example 469: N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-(((1R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl)amino)-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0879
  • Example 469 was made analogously to Example 333 using (1R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2-amine in place of tert-butyl (2-aminoethyl)carbamate. The TFA salt of N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-(((1R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl)amino)-1H-benzo[d]imidazole-7-carboximidamide was isolated as an off-white solid. C22H22ClF3N6O. 479.3/481.1 (M+1). 1H NMR (400 MHz, DMSO-d6, 2:1 mixture of diastereomers) δ 10.82 (br. s, 1H), 9.72 (s, 1H), 8.69 (d, J = 7.8 Hz, 1H), 7.17 - 7.03 (m, 2H), 6.90 (td, J = 6.5, 2.8 Hz, 1H), 6.81 (dd, J = 12.3, 7.0 Hz, 1H), 6.55 (ddd, J = 8.9, 4.6, 3.1 Hz, 1H), 4.29 (m, 1H), 4.05 - 3.70 (m, 2H), 2.75 (d, J = 4.9 Hz, '2H'), 2.63 (d, J = 4.8 Hz, '1H'), 2.23 (m, 1H), 2.14 - 1.80 (m, 5H), 1.73 (m, 1H), 1.54 (m, 1H). 19F NMR (377 MHz, DMSO) δ -75.02, Major: -127.83, -150.68,-156.90, Minor: -127.66, -150.46, -156.51
    • Example 470: (S)-N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((2-(2-(trifluoromethyl)pyrrolidin-1-yl)ethyl)amino)-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0880
  • Example 470 was made analogously to Example 333 using (S)-2-(2-(trifluoromethyl)pyrrolidin-1-yl)ethan-1-amine in place of tert-butyl (2-aminoethyl)carbamate. The TFA salt of (S)-N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((2-(2-(trifluoromethyl)pyrrolidin-1-yl)ethyl)amino)-1H-benzo[d]imidazole-7-carboximidamide was isolated as an off-white solid. C21H19ClF6N6O. 521.3/523.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 10.99 (br. s, 1H), 8.82 (s, 1H), 7.95 (br. s, 1H), 7.13 - 7.03 (m, 2H), 6.97 (dd, J = 6.5, 2.7 Hz, 1H), 6.54 (ddd, J = 9.0, 4.1, 2.8 Hz, 1H), 3.59 - 3.40 (m, 3H), 3.19 (m, 1H), 3.03 (dt, J = 13.6, 7.1 Hz, 1H), 2.82 (dt, J = 12.7, 5.2 Hz, 1H), 2.46 (m, 1H), 2.04 (m, 1H), 1.87 - 1.64 (m, 3H). 19F NMR (377 MHz, DMSO-d6) δ -75.31 (9F), -75.43 (d, J = 8.2 Hz, 3F), -126.82 (1F), -147.12 (1F), -155.04 (1F).
    • Example 471: N-(3-chloro-4-fluorophenyl)-4,5-difluoro-2-(((hexahydro-1H-pyrrolizin-7a-yl)methyl)amino)-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0881
  • Example 471 was made analogously to Example 333 using (tetrahydro-1H-pyrrolizin-7a(5H)-yl)methanamine in place of tert-butyl (2-aminoethyl)carbamate. The TFA salt of N-(3-chloro-4-fluorophenyl)-4,5-difluoro-2-(((hexahydro-1H-pyrrolizin-7a-yl)methyl)amino)-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide was isolated as an off-white solid. C22H22ClF3N6O. 479.4/481.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 10.75 (br. s, 1H), 8.74 (s, 1H), 7.08 (t, J = 9.1 Hz, 1H), 6.93 (dd, J = 6.5, 2.7 Hz, 1H), 6.87 (dd, J = 12.2, 7.1 Hz, 1H), 6.50 (dq, J = 9.0, 3.0 Hz, 1H), 3.69 (app. d, J = 5.9 Hz, 2H), 3.46 (dq, J = 12.0, 6.1 Hz, 2H), 3.20 (m, 2H), 2.14 - 1.96 (m, 4H), 1.95 - 1.80 (m, 4H). 19F NMR (377 MHz, DMSO-d6) δ -75.1 (9F), -127.3 (1F), -149.9 (dd, J = 22.6, 12.3 Hz, 1F), -156.8 (1F).
    • Example 472: N-(3-chloro-4-fluorophenyl)-2-(((3,3-dimethylazetidin-2-yl)methyl)amino)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0882
  • Example 472 was made analogously to Example 333 using tert-butyl 2-(aminomethyl)-3,3-dimethylazetidine-1-carboxylate in place of tert-butyl (2-aminoethyl)carbamate. The TFA salt of N-(3-chloro-4-fluorophenyl)-2-(((3,3-dimethylazetidin-2-yl)methyl)amino)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide was isolated as an off-white solid. C20H20ClF3N6O. 453.2/455.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 10.80 (s, 1H), 8.97 (br. s, 1H), 8.75 - 8.65 (m, 2H), 7.09 (t, J = 9.1 Hz, 1H), 6.97 - 6.78 (m, 3H), 6.53 (ddd, J = 9.0, 4.1, 2.8 Hz, 1H), 4.24 (m, 1H), 3.80 - 3.59 (m, 3H), 3.49 (m, 1H), 1.27 (s, 3H), 1.22 (s, 3H). 19F NMR (377 MHz, DMSO-d6) δ -75.0 (9F), -127.3 (1F), -150.3 (1F), -156.7 (d, J = 23.0 Hz, 1F).
    • Example 473: N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((4-(pyrrolidin-1-yl)tetrahydro-2H-pyran-3-yl)amino)-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0883
  • Example 473 was made analogously to Example 333 using 4-(pyrrolidin-1-yl)tetrahydro-2H-pyran-3-amine in place of tert-butyl (2-aminoethyl)carbamate. The TFA salt of N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((4-(pyrrolidin-1-yl)tetrahydro-2H-pyran-3-yl)amino)-1H-benzo[d]imidazole-7-carboximidamide was isolated as an off-white solid. C23H24ClF3N6O2. 509.3/511.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 10.79 (s, 1H), 9.65 (br. s, 1H), 8.68 (s, 1H), 7.20 (d, J = 8.0 Hz, 1H), 7.11 (t, J = 9.1 Hz, 1H), 6.91 (dd, J = 6.5, 2.7 Hz, 1H), 6.84 (dd, J = 12.3, 6.8 Hz, 1H), 6.54 (ddd, J = 9.0, 4.0, 2.8 Hz, 1H), 4.35 (s, 1H), 4.04 (dd, J = 12.5, 3.2 Hz, 1H), 3.83 - 3.73 (m, 2H), 3.66 (m, 1H), 3.55 - 3.40 (m, 5H), 2.13 (m, 1H), 2.00 - 1.85 (m, 4H), 1.71 (m, 1H). 19F NMR (377 MHz, DMSO-d6) δ -74.93 (9F), -127.54 (1F), -150.41 (1F), -156.80 (1F).
    • Example 474: 2-(((1S,2R)-2-aminocyclohexyl)amino)-N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0884
  • Example 474 was made analogously to Example 333. The TFA salt of 2-(((1S,2R)-2-aminocyclohexyl)amino)-N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide was isolated as an off-white solid. C20H20ClF3N6O. 453.2/455.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 10.79 (s, 1H), 8.64 (s, 1H), 7.78 (br. s, 3H), 7.12 (t, J = 9.1 Hz, 1H), 6.95 (d, J = 8.5 Hz, 1H), 6.88 (dd, J = 6.5, 2.7 Hz, 1H), 6.76 (dd, J = 12.3, 6.8 Hz, 1H), 6.53 (ddd, J = 9.0, 3.9, 2.6 Hz, 1H), 4.27 (m, 1H), 3.45 (m, 1H), 1.81 - 1.60 (m, 4H), 1.58 - 1.31 (m, 4H). 19F NMR (376 MHz, DMSO-d6) δ -74.8, -127.66, -150.5, -156.8.
    • Example 475: N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)amino)-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0885
  • Example 475 was made analogously to Example 333 using 2-methyl-1,2,3,4-tetrahydroisoquinolin-4-amine in place of tert-butyl (2-aminoethyl)carbamate. The TFA salt of N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)amino)-1H-benzo[d]imidazole-7-carboximidamide was isolated as an off-white solid. C24H20ClF3N6O. 501.3/503.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 10.78 (s, 1H), 10.32 (br. s, 1H), 8.69 (s, 1H), 7.49 (m, 1H), 7.45 - 7.34 (m, 2H), 7.30 - 7.20 (m, 2H), 7.07 (m, 1H), 6.95 - 6.80 (m, 2H), 6.51 (m, 1H), 5.62 (m, 1H), 5.16 (m, 1H), 4.61 (m, 1H), 4.37 (m, 1H), 3.40 (m, 1H), 3.03 (s, 3H). 19F NMR (376 MHz, DMSO-d6) δ -74.8, -127.4, -150.0 -156.9.
    • Example 476: N-(3-chloro-4-fluorophenyl)-2-(((3S,4S)-4-(diethylamino)tetrahydrofuran-3-yl)amino)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0886
  • Example 476 was made analogously to Example 333 using (3S,4S)-N 3,N 3-diethyltetrahydrofuran-3,4-diamine. The TFA salt of N-(3-chloro-4-fluorophenyl)-2-(((3S*,4S*)-4-(diethylamino)tetrahydrofuran-3-yl)amino)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide was isolated as an off-white solid. C22H24ClF3N6O2. 497.3/499.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 10.77 (s, 1H), 10.18 (br. s, 1H), 8.69 (s, 1H), 7.38 (s, 1H), 7.08 (t, J = 9.1 Hz, 1H), 6.97 - 6.81 (m, 2H), 6.53 (dt, J = 9.0, 3.4 Hz, 1H), 4.63 (m, 1H), 4.21 (m, 1H), 4.15 - 4.03 (m, 2H), 3.59 (m, 2H), 3.40 - 3.20 (m, 4H), 1.23 (t, J = 7.2 Hz, 6H). 19F NMR (376 MHz, DMSO-d6) δ-74.9, -127.4, -150.1, -157.2.
    • Example 477: 2-((1,4-oxazepan-6-yl)amino)-N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0887
  • Example 477 was made analogously to Example 333 using tert-butyl 6-amino-1,4-oxazepane-4-carboxylate in place of tert-butyl (2-aminoethyl)carbamate. The TFA salt of 2-((1,4-oxazepan-6-yl)amino)-N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide was isolated as an off-white solid. C19H18ClF3N6O2. 455.2/457.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 10.81 (s, 1H), 9.01 (br. s, 2H), 8.69 (s, 1H), 7.11 (t, J = 9.1 Hz, 1H), 6.97 (d, J = 7.3 Hz, 1H), 6.91 (dd, J = 6.5, 2.7 Hz, 1H), 6.82 (dd, J = 12.3, 6.9 Hz, 1H), 6.53 (ddd, J = 9.0, 4.1, 2.8 Hz, 1H), 4.33 (m, 1H), 3.99 - 3.74 (m, 4H), 3.54 (m, 1H), 3.46 (m, 1H), 3.32 (m, 1H). 19F NMR (377 MHz, DMSO-d6) δ -74.9 (9F), -127.5 (1F), -150.5 (1F), -156.8 (1F).
    • Example 478: N-(3-chloro-4-fluorophenyl)-2-((2-((2S,6R)-2,6-dimethylmorpholino)ethyl)amino)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0888
  • Example 478 was made analogously to Example 229 using 3-(2-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one and 2-((2S,6R)-2,6-dimethylmorpholino)ethan-1-amine in place of 3-(2-chloro-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one and 3-aminopropanamide hydrochloride, respectively. The TFA salt of N-(3-chloro-4-fluorophenyl)-2-((2-((2S,6R)-2,6-dimethylmorpholino)ethyl)amino)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide was isolated as an off-white solid. C21H25ClFN7O2. 462.3/464.2 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 11.40 (br. s, 1H), 8.98 (s, 1H), 8.20 (br. s, 1H), 8.00 (d, J = 6.2 Hz, 1H), 7.10 (t, J = 9.0 Hz, 1H), 7.02 (dd, J = 6.5, 2.7 Hz, 1H), 6.95 (d, J = 6.2 Hz, 1H), 6.57 (ddd, J = 8.9, 4.0, 2.7 Hz, 1H), 3.88 - 3.78 (m, 4H), 3.63 - 3.53 (m, 2H), 3.40 - 3.31 (m, 2H), 2.77 - 2.61 (m, 2H), 1.15 (d, J = 6.3 Hz, 6H). 19F NMR (377 MHz, DMSO-d6) δ -74.60 (9F), -126.59 (IF).
    • Example 479: N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(((3R,4R)-4-methoxy-1-methylpyrrolidin-3-yl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0889
  • Example 479 was made analogously to Example 333 using (3R,4R)-4-methoxy-1-methylpyrrolidin-3-amine in place of 3-(2-chloro-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one and 3-aminopropanamide hydrochloride, respectively. The TFA salt of N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(((3R,4R)-4-methoxy-1-methylpyrrolidin-3-yl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide was isolated as an off-white solid. C19H21ClFN7O2. 434.2/436.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 11.25 (br. s, 1H), 10.23 (br. s, 1H), 8.92 (s, 1H), 7.98 (s, 1H), 7.09 (t, J = 9.0 Hz, 1H), 7.03 - 6.90 (m, 2H), 6.67 (m, 1H), 4.49 (m, 1H), 4.11 (m, 1H), 3.97 (m, 1H), 3.72 (m, 1H), 3.36 (s, 3H), 3.30 - 3.04 (m, 2H), 2.90 (s, 3H). 19F NMR (377 MHz, DMSO-d6) δ -74.4, -126.7.
    • Example 480: N-(3-chloro-4-fluorophenyl)-2-(((3R,4R)-4-(diethylamino)tetrahydrofuran-3-yl)amino)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0890
  • Example 480 was made analogously to Example 229 using 3-(2-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one and (3R,4R)-N3,N3-diethyltetrahydrofuran-3,4-diamine in place of 3-(2-chloro-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one and 3-aminopropanamide hydrochloride, respectively. The TFA salt of N-(3-chloro-4-fluorophenyl)-2-(((3R,4R)-4-(diethylamino)tetrahydrofuran-3-yl)amino)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide was isolated as an off-white solid. C21H25ClFN7O2. 462.2/464.2 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 11.20 (br. s, 1H), 8.86 (s, 1H), 7.96 (s, 2H), 7.07 (s, 1H), 7.00 - 6.85 (m, 1H), 6.53 (s, 1H), 4.65 (m, 1H), 4.21 (m, 1H), 4.16 - 4.05 (m, 2H), 3.36 - 3.22 (m, 4H), 1.24 (t, J = 7.2 Hz, 6H).
    • Example 481: (S)-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((2-(2-(trifluoromethyl)pyrrolidin-1-yl)ethyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0891
  • Example 481 was made analogously to Example 229 using 3-(2-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one and (S)-2-(2-(trifluoromethyl)pyrrolidin-1-yl)ethan-1-amine in place of 3-(2-chloro-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one and 3-aminopropanamide hydrochloride, respectively. The TFA salt of (S)-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((2-(2-(trifluoromethyl)pyrrolidin-1-yl)ethyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide was isolated as an off-white solid. C20H20ClF4N7O. 486.3/488.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 11.41 (br. s, 1H), 8.95 (s, 1H), 7.97 (d, J = 6.4 Hz, 1H), 7.10 (t, J = 9.0 Hz, 1H), 7.02 (dd, J = 6.5, 2.7 Hz, 1H), 6.94 (d, J = 6.3 Hz, 1H), 6.59 (dt, J = 9.0, 3.5 Hz, 1H), 3.60 - 3.50 (m, 2H), 3.18 (m, 1H), 3.06 (m, 1H), 2.81 (dt, J = 11.6, 5.4 Hz, 1H), 2.45 (m, 1H), 2.02 (m, 1H), 1.87 - 1.64 (m, 4H). 19F NMR (376 MHz, DMSO-d6) δ -74.5 , -75.5, -126.5.
    • Example 482: (R)-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(((4-methylmorpholin-3-yl)methyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0892
  • Example 482 was made analogously to Example 229 using 3-(2-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one and (R)-(4-methylmorpholin-3-yl)methanamine in place of 3-(2-chloro-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one and 3-aminopropanamide hydrochloride, respectively. The TFA salt of (R)-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(((4-methylmorpholin-3-yl)methyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide was isolated as an off-white solid. C19H21ClFN7O2. 434.2/436.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 8.87 (br. s, 1H), 7.95 (s, 1H), 7.09 (t, J = 8.9 Hz, 1H), 7.05 - 6.8 (m, 2H), 6.57 (dt, J = 9.0, 3.4 Hz, 1H), 4.09 - 3.88 (m, 2H), 3.69 - 3.40 (m, 7H), 2.98 (s, 3H).
    • Example 483: N-(3-chloro-4-fluorophenyl)-2-((2-(2,6-dimethylmorpholino)propyl)amino)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0893
  • Example 483 was made analogously to Example 229 using 3-(2-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one and 2-(2,6-dimethylmorpholino)propan-1-amine in place of 3-(2-chloro-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one and 3-aminopropanamide hydrochloride, respectively. The TFA salt of N-(3-chloro-4-fluorophenyl)-2-((2-(2,6-dimethylmorpholino)propyl)amino)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide was isolated as an off-white solid. C22H27ClFN7O2. 476.3/478.2 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 11.80 (br. s, 1H), 11.31 (br. s, 1H), 8.95 (s, 1H), 7.99 (d, J = 6.0 Hz, 1H), 7.10 (t, J = 9.0 Hz, 1H), 7.00 (dd, J = 6.6, 2.7 Hz, 1H), 6.93 (d, J = 6.0 Hz, 1H), 6.57 (ddd, J = 9.0, 4.0, 2.7 Hz, 1H), 3.98 - 3.66 (m, 7H), 2.83 - 2.65 (m, 2H), 1.28 (d, J = 6.6 Hz, 3H), 1.17 (d, J = 4.3 Hz, 3H), 1.15 (d, J = 4.2 Hz, 3H). 19F NMR (377 MHz, DMSO-d6) δ -74.5 (9H), -126.8 (1H).
    • Example 484: N-(3-chloro-4-fluorophenyl)-2-((2-(2,6-dimethylmorpholino)-2-methylpropyl)amino)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0894
  • Example 484 was made analogously to Example 229 using 3-(2-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one and 2-(2,6-dimethylmorpholino)-2-methylpropan-1-amine in place of 3-(2-chloro-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one and 3-aminopropanamide hydrochloride, respectively. The TFA salt of N-(3-chloro-4-fluorophenyl)-2-((2-(2,6-dimethylmorpholino)-2-methylpropyl)amino)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide was isolated as an off-white solid. C23H29ClFN7O2. 490.2/492.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 11.60 (br. s, 1H), 11.27 (br. s, 1H), 8.89 (s, 1H), 7.99 (d, J = 6.0 Hz, 1H), 7.10 (t, J = 9.0 Hz, 1H), 7.00 (dd, J = 6.5, 2.7 Hz, 1H), 6.92 (d, J = 6.0 Hz, 1H), 6.57 (ddd, J = 8.9, 3.9, 2.7 Hz, 1H), 4.00 - 3.85 (m, 2H), 3.78 - 3.50 (m, 4H), 2.70 (m, 2H), 1.32 (s, 6H), 1.19 (s, 3H), 1.17 (s, 3H). 19F NMR (376 MHz, DMSO-d6) δ -74.51 (9F),-126.81 (1F).
    • Example 485: N-(3-chloro-4-fluorophenyl)-2-((2-(2,5-dimethylmorpholino)ethyl)amino)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0895
  • Example 485 was made analogously to Example 229 using 3-(2-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one and 2-(2,5-dimethylmorpholino)ethan-1-amine in place of 3-(2-chloro-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one and 3-aminopropanamide hydrochloride, respectively. The TFA salt of N-(3-chloro-4-fluorophenyl)-2-((2-(2,5-dimethylmorpholino)ethyl)amino)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide was isolated as an off-white solid. C21H25ClFN7O2. 462.3/464.2 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 11.28 (br. s, 1H), 8.92 (m, 1H), 7.99 (d, J = 6.0 Hz, 1H), 7.10 (t, J = 9.0 Hz, 1H), 6.99 (d, J = 6.3 Hz, 1H), 6.93 (t, J = 6.8 Hz, 1H), 6.58 (ddd, J = 9.3, 4.4, 2.9 Hz, 1H), 4.00 - 3.75 (m, 6H), 3.37 - 3.17 (m, 2H), 2.93 (m, 2H), 1.33 (d, J = 6.8 Hz, 2H), 1.16 (d, J = 6.2 Hz, 4H). 19F NMR (376 MHz, DMSO-d6) δ -74.5, -126.6.
    • Example 486: N-(3-chloro-4-fluorophenyl)-2-(((1R,2R)-2-(dimethylamino)cyclopentyl)amino)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0896
  • Example 486 was made analogously to Example 333 using (1R,2R)-N1,N1-dimethylcyclopentane-1,2-diamine in place of tert-butyl (2-aminoethyl)carbamate. The TFA salt of N-(3-chloro-4-fluorophenyl)-2-(((1R,2R)-2-(dimethylamino)cyclopentyl)amino)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide was isolated as an off-white solid. C21H22ClF3N6O. 467.3/469.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 10.74 (br. s, 1H), 8.69 (s, 1H), 7.09 (t, J = 9.0 Hz, 1H), 6.91 (dd, J = 6.5, 2.7 Hz, 1H), 6.84 (m, 1H), 6.52 (m, 1H), 4.34 (m, 1H), 3.61 (m, 1H), 2.85 (s, 6H), 2.17 - 1.96 (m, 2H), 1.89 (m, 1H), 1.80 - 1.59 (m, 3H). 19F NMR (376 MHz, DMSO-d6) δ -74.8, -127.4, -150.3, -157.2.
    • Example 487: N-(3-chloro-4-fluorophenyl)-2-((2-(dimethylamino)ethyl)thio)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0897
  • To a solution of 2-(dimethylamino)ethane-1-thiol (0.01 mL, 0.096 mmol, 1.9 equiv) in 0.5 mL THF at -78 °C was added 0.04 mL of n-BuLi (0.06 mmol, 1.6 equiv). The mixture was stirred for 10 minutes before the addition of 3-(2-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one (25 mg, 0.05 mmol, 1 equiv) in 0.5 mL of THF. The reaction was slowly warmed to room temperature and stirred for 3 hours before being quenched with saturated aqueous NH4Cl. The reaction mixture was extracted twice with EtOAc, the combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. The crude product was dissolved in 0.75 mL CH2Cl2 and 0.75 mL of TFA was added. The reaction was stirred at room temperature for 3 hours before being concentrated in vacuo. The crude product was then dissolved in 0.4 mL THF, 0.4 mL MeOH and 0.9 mL of 2N aqueous NaOH was added. The reaction was stirred at room temperature for 30 minutes before being neutralized with 0.9 mL of 2N aqueous HCl, diluted with DMF and purified by reverse phase HPLC. The TFA salt of N-(3-chloro-4-fluorophenyl)-2-((2-(dimethylamino)ethyl)thio)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide was isolated as an off-white solid. C17H18ClFN6OS. 409.3/411.0 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 10.99 (br. s, 1H), 8.87 (s, 1H), 8.21 (d, J = 5.2 Hz, 1H), 7.15 - 7.00 (m, 2H), 6.93 (dd, J = 6.6, 2.7 Hz, 1H), 6.50 (ddd, J = 8.9, 4.0, 2.7 Hz, 1H), 3.70 - 3.55 (m, 2H), 3.55 - 3.45 (m, 2H), 2.89 (s, 6H). 19F NMR (376 MHz, DMSO-d6) δ -74.69 (9F), -127.08 (1F).
    • Example 488: N-(3-chloro-4-fluorophenyl)-2-((2-(dimethylamino)ethyl)thio)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0898
  • Example 488 was made analogously to Example 212 using 3-(2-chloro-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one. The TFA salt of N-(3-chloro-4-fluorophenyl)-2-((2-(dimethylamino)ethyl)thio)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide was isolated as an off-white solid. C18H17ClF3N5OS. 444.3/446.0 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 12.91 (br. s, 1H), 10.83 (br. s, 1H), 9.65 (s, 1H), 8.76 (s, 1H), 7.18 - 7.00 (m, 2H), 6.96 (dd, J = 6.6, 2.7 Hz, 1H), 6.49 (ddd, J = 9.0, 4.1, 2.7 Hz, 1H), 3.61 - 3.44 (m, 4H), 2.87 (d, J = 3.0 Hz, 6H). 19F NMR (377 MHz, DMSO-d6) δ -74.5 (6F), -127.0 (1F), -149.5 (1F), -154.15 (1F).
    • Example 489: N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((2-(2-(hydroxymethyl)piperidin-1-yl)ethyl)amino)-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0899
  • Example 489 was made analogously to Example 333 using (1-(2-aminoethyl)piperidin-2-yl)methanol in place of tert-butyl (2-aminoethyl)carbamate. The TFA salt of N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((2-(2-(hydroxymethyl)piperidin-1-yl)ethyl)amino)-1H-benzo[d]imidazole-7-carboximidamide was isolated as an off-white solid. C22H24ClF3N6O2. 497.3/499.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 10.80 (s, 1H), 9.56 (br. s, 1H), 8.72 (s, 1H), 7.09 (t, J = 9.1 Hz, 1H), 6.98 (s, 1H), 6.94 (dd, J = 6.5, 2.7 Hz, 1H), 6.85 (dd, J = 12.2, 6.9 Hz, 1H), 6.52 (ddd, J = 9.0, 4.1, 2.7 Hz, 1H), 3.88 (m, 1H), 3.80 - 3.65 (m, 2H), 3.60 - 3.40 (m, 3H), 3.35 - 3.20 (m, 2H), 3.13 (m, 1H), 1.90 - 1.65 (m, 5H), 1.50 (m, 1H). 19F NMR (377 MHz, DMSO-d6) δ -75.1 (9F), -127.3 (1F), -150.2 (1F), -156.9 (1F).
    • Example 490: N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((2-(2-(hydroxymethyl)pyrrolidin-1-yl)ethyl)amino)-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0900
  • Example 490 was made analogously to Example 333 using (1-(2-aminoethyl)pyrrolidin-2-yl)methanol in place of tert-butyl (2-aminoethyl)carbamate. The TFA salt of N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((2-(2-(hydroxymethyl)pyrrolidin-1-yl)ethyl)amino)-1H-benzo[d]imidazole-7-carboximidamide was isolated as an off-white solid. C21H22ClF3N6O2. 483.3/485.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 10.79 (br. s, 1H), 9.82 (br. s, 1H), 8.70 (s, 1H), 7.09 (t, J = 9.1 Hz, 1H), 7.02 (s, 1H), 6.94 (dd, J = 6.6, 2.7 Hz, 1H), 6.85 (dd, J = 12.2, 6.9 Hz, 1H), 6.53 (ddd, J = 9.0, 4.1, 2.7 Hz, 1H), 3.78 - 3.64 (m, 4H), 3.63 - 3.50 (m, 3H), 3.35 (m, 1H), 3.19 (m, 1H), 2.14 - 1.95 (m, 2H), 1.90 (m, 1H), 1.75 (m, 1H). 19F NMR (376 MHz, DMSO-d6) δ -75.1 , -127.3, -150.2, -156.9.
    • Example 491: N-(3-chloro-4-fluorophenyl)-2-((2-(3,3-difluoropyrrolidin-1-yl)ethyl)amino)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0901
  • Example 491 was made analogously to Example 229 using 3-(2-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one and 2-(3,3-difluoropyrrolidin-1-yl)ethan-1-amine in place of 3-(2-chloro-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one and 3-aminopropanamide hydrochloride, respectively. The TFA salt of N-(3-chloro-4-fluorophenyl)-2-((2-(3,3-difluoropyrrolidin-1-yl)ethyl)amino)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide was isolated as an off-white solid. C19H19ClF3N7O. 454.3/456.2 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 11.40 (br. s, 1H), 8.97 (s, 1H), 7.98 (d, J = 6.2 Hz, 1H), 7.11 (t, J = 9.0 Hz, 1H), 7.03 (dd, J = 6.5, 2.7 Hz, 1H), 6.94 (d, J = 6.2 Hz, 1H), 6.59 (ddd, J = 8.9, 4.0, 2.7 Hz, 1H), 3.62 (m, 2H), 3.34 (m, 2H), 3.18 - 2.89 (m, 4H), 2.45 - 2.28 (m, 2H). 19F NMR (377 MHz, DMSO-d6) δ - 74.7 (9F), -92.1 (2F), -126.6 (1F).
    • Example 492: N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((2-sulfamoylethyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0902
  • Example 492 was made analogously to Example 229 using 3-(2-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one and 2-aminoethane-1-sulfonamide in place of 3-(2-chloro-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one and 3-aminopropanamide hydrochloride, respectively. The TFA salt of N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((2-sulfamoylethyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide was isolated as an off-white solid. C15H15ClFN7O3S. 428.1/430.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 12.00 (br. s, 1H), 11.47 (br. s, 1H), 8.99 (s, 1H), 7.97 (d, J = 6.4 Hz, 1H), 7.11 (t, J = 9.0 Hz, 1H), 7.06 (s, 2H), 7.04 (dd, J = 6.8, 3.0 Hz, 1H), 6.92 (d, J = 6.4 Hz, 1H), 6.59 (ddd, J = 8.9, 4.0, 2.8 Hz, 1H), 3.87 (q, J = 6.5 Hz, 2H), 3.35 (t, J = 6.6 Hz, 2H). 19F NMR (377 MHz, DMSO-d6) δ -74.6 (6F), -126.5 (1F).
    • Example 493: N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((2-(methylsulfonyl)ethyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0903
  • Example 493 was made analogously to Example 229 using 3-(2-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one and 2-(methylsulfonyl)ethan-1-amine in place of 3-(2-chloro-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one and 3-aminopropanamide hydrochloride, respectively. The TFA salt of N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((2-(methylsulfonyl)ethyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide was isolated as an off-white solid. C16H16ClFN6O3S. 427.1/429.0 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 11.46 (br. s, 1H), 8.97 (s, 1H), 7.99 (d, J = 6.3 Hz, 1H), 7.11 (t, J = 9.0 Hz, 1H), 7.04 (dd, J = 6.5, 2.7 Hz, 1H), 6.95 (d, J = 6.3 Hz, 1H), 6.59 (dq, J = 8.8, 3.0 Hz, 1H), 3.91 (q, J = 6.4 Hz, 2H), 3.51 (d, J = 6.4 Hz, 2H), 3.07 (s, 3H). 19F NMR (376 MHz, DMSO-d6) δ -74.6 (6F), -126.5 (1F).
    • Example 494: N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((pyrimidin-2-ylmethyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0904
  • Example 494 was made analogously to Example 229 using 3-(2-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one and pyrimidin-2-ylmethanamine in place of 3-(2-chloro-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one and 3-aminopropanamide hydrochloride, respectively. The TFA salt of N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((pyrimidin-2-ylmethyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide was isolated as an off-white solid. C18H14ClFN8O. 413.2/415.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 11.49 (br. s, 1H), 9.00 (s, 1H), 8.83 (d, J = 4.9 Hz, 2H), 7.99 (d, J = 6.3 Hz, 1H), 7.48 (t, J = 4.9 Hz, 1H), 7.11 (t, J = 9.0 Hz, 1H), 7.05 (dd, J = 6.5, 2.7 Hz, 1H), 6.95 (d, J = 6.3 Hz, 1H), 6.60 (dt, J = 8.9, 3.3 Hz, 1H), 4.91 (d, J = 5.9 Hz, 2H). 19F NMR (377 MHz, DMSO-d6) δ -74.7 (6F), -126.6 (1F).
    • Example 495: (R)-N-(3-chlorophenyl)-4,5-difluoro-N'-hydroxy-2-((1-(2-methoxyethyl)pyrrolidin-3-yl)amino)-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0905
  • Example 495 was made analogously to Example 333 using (R)-1-(2-methoxyethyl)pyrrolidin-3-amine dihydrochloride and N-ethyl-N-isopropylpropan-2-amine in place of tert-butyl (2-aminoethyl)carbamate and 3-(2-chloro-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-7-yl)-4-(3-chlorophenyl)-1,2,4-oxadiazol-5(4H)-one in place of 3-(2-chloro-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one. The TFA salt of (R)-N-(3-chlorophenyl)-4,5-difluoro-N'-hydroxy-2-((1-(2-methoxyethyl)pyrrolidin-3-yl)amino)-1H-benzo[d]imidazole-7-carboximidamide was isolated as an off-white solid. C21H23ClF2N6O2. 465.2/467.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 10.87 (s, 1H), 10.20 (br. s, 1H), 8.74 (s, 1H), 7.26 (m, 1H), 7.04 (m, 1H), 6.82 (m, 2H), 6.50 (m, 1H), 4.65 - 4.40 (m, 1H), 3.98 - 3.70 (m, 1H), 3.68 - 3.55 (m, 3H), 3.51 - 3.36 (m, 2H), 3.33 (m, 3H), 3.13 (m, 2H), 2.10 - 1.85 (m, 2H). 19F NMR (377 MHz, DMSO-d6) δ -75.0 (9F), -150.3 (1F), -156.7 (1F).
    • Example 496: (R)-N-(3-bromophenyl)-4,5-difluoro-N'-hydroxy-2-((1-(2-methoxyethyl)pyrrolidin-3-yl)amino)-1H-benzo[d]imidazole-7-carboximidamide
  • Figure imgb0906
  • Example 496 was made analogously to Example 333 using (R)-1-(2-methoxyethyl)pyrrolidin-3-amine dihydrochloride and N-ethyl-N-isopropylpropan-2-amine in place of tert-butyl (2-aminoethyl)carbamate and 4-(3-bromophenyl)-3-(2-chloro-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-7-yl)-1,2,4-oxadiazol-5(4H)-one in place of 3-(2-chloro-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one. The TFA salt of (R)-N-(3-bromophenyl)-4,5-difluoro-N'-hydroxy-2-((1-(2-methoxyethyl)pyrrolidin-3-yl)amino)-1H-benzo[d]imidazole-7-carboximidamide was isolated as an off-white solid. C21H23BrF2N6O2. 509.2/511.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 10.84 (s, 1H), 10.18 (br. s, 1H), 8.69 (d, J = 2.6 Hz, 1H), 7.17 (m, 1H), 7.05 (m, 1H), 7.00 - 6.91 (m, 3H), 6.84 (dd, J = 12.3, 6.9 Hz, 1H), 6.55 (dt, J = 7.7, 1.7 Hz, 1H), 4.65 - 4.35 (m, 1H), 4.00 - 3.70 (m, 1H), 3.65 - 3.55 (m, 3H), 3.51 - 3.36 (m, 2H), 3.32 (m, 3H), 3.12 (m, 2H), 2.11 - 1.85 (m, 2H). 19F NMR (376 MHz, DMSO-d6) δ -75.0 (9F), -150.4 (9F), -156.7 (9F).
    • Example 497: (S)-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((1-(oxetan-3-yl)piperidin-3-yl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0907
  • Example 497 was made analogously to Example 229 using 3-(2-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one and (S)-1-(oxetan-3-yl)piperidin-3-amine in place of 3-(2-chloro-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one and 3-aminopropanamide hydrochloride, respectively. The TFA salt of (S)-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((1-(oxetan-3-yl)piperidin-3-yl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide was isolated as an off-white solid. C21H23ClFN7O2. 460.2/462.2 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 11.39 (br. s, 1H), 8.95 (s, 1H), 8.16 (br. s, 1H), 7.98 (d, J = 6.2 Hz, 1H), 7.11 (t, J = 9.0 Hz, 1H), 7.02 (dd, J = 6.5, 2.7 Hz, 1H), 6.94 (d, J = 6.2 Hz, 1H), 6.59 (dt, J = 8.9, 3.5 Hz, 1H), 4.75 - 4.65 (m, 4H), 4.20 - 4.05 (m, 2H), 3.80 - 3.55 (m, 2H), 2.85 - 2.60 (m, 2H), 2.05 - 1.85 (m, 2H), 1.81 - 1.45 (m, 2H). 19F NMR (376 MHz, DMSO-d6) δ -74.6, -126.7.
    • Example 498: N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((1-(2-methoxyethyl)piperidin-3-yl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0908
  • Example 498 was made analogously to Example 229 using 3-(2-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one and 1-(2-methoxyethyl)piperidin-3-amine in place of 3-(2-chloro-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one and 3-aminopropanamide hydrochloride, respectively. The TFA salt of N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((1-(2-methoxyethyl)piperidin-3-yl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide was isolated as an off-white solid. C21H25ClFN7O2. 462.1/464.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 9.70 (br. s, 1H), 8.89 (br. s, 1H), 7.96 (s, 1H), 7.10 (t, J = 9.0 Hz, 1H), 6.98 (m, 1H), 6.90 (m, 1H), 6.58 (dt, J = 8.9, 3.5 Hz, 1H), 4.20 (m, 1H), 3.75 - 3.60 (m, 2H), 3.50 - 3.25 (m, 4H), 3.32 (s, 3H), 2.95-2.80 (m, 2H), 2.09 - 1.73 (m, 3H), 1.51 (m, 1H). 19F NMR (376 MHz, DMSO-d6) δ-74.31, -126.85.
    • Example 499: N-(3-chloro-4-fluorophenyl)-2-((1-cyclopropylpyrrolidin-3-yl)amino)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0909
  • Example 499 was made analogously to Example 229 using 3-(2-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one and 1-cyclopropylpyrrolidin-3-amine trifluoroacetic acid salt (1:2) and N-ethyl-N-isopropylpropan-2-amine in place of 3-(2-chloro-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one and 3-aminopropanamide hydrochloride, respectively. The TFA salt of N-(3-chloro-4-fluorophenyl)-2-((1-cyclopropylpyrrolidin-3-yl)amino)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide was isolated as an off-white solid. C20H21ClFN7O. 430.1/432.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 11.21 (br. s, 1H), 8.89 (s, 1H), 7.96 (m, 1H), 7.08 (t, J = 9.1 Hz, 1H), 7.05 - 6.80 (m, 2H), 6.57 (dt, J = 8.9, 3.5 Hz, 1H), 4.60 - 4.45 (m, 2H), 3.95 - 3.45 (m, 4H), 3.05 - 2.90 (m, 2H), 1.00 - 0.75 (m, 4H).
    • Example 500: (R)-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((1-(oxetan-3-yl)piperidin-3-yl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0910
  • Example 500 was made analogously to Example 229 using 3-(2-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one and (R)-1-(oxetan-3-yl)piperidin-3-amine in place of 3-(2-chloro-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one and 3-aminopropanamide hydrochloride, respectively. The TFA salt of (R)-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((1-(oxetan-3-yl)piperidin-3-yl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide was isolated as an off-white solid. C21H23ClFN7O2. 460.2/462.2 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 11.39 (br. s, 1H), 8.95 (s, 1H), 8.17 (br. s, 1H), 7.98 (d, J = 6.2 Hz, 1H), 7.11 (t, J = 9.0 Hz, 1H), 7.02 (dd, J = 6.5, 2.7 Hz, 1H), 6.93 (d, J = 6.2 Hz, 1H), 6.59 (dt, J = 8.9, 3.5 Hz, 1H), 4.75 - 4.55 (m, 4H), 4.20 - 4.05 (m, 2H), 3.80 - 3.60 (m, 2H), 2.84 - 2.59 (m, 2H), 2.10 - 1.80 (m, 2H), 1.80 - 1.51 (m, 2H). 19F NMR (377 MHz, DMSO-d6) δ -74.6 (9F), -126.8 (1F).
    • Example 501: N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((2-(4-methyl-3-oxopiperazin-1-yl)ethyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0911
  • Example 501 was made analogously to Example 229 using 3-(2-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one and 4-(2-aminoethyl)-1-methylpiperazin-2-one in place of 3-(2-chloro-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one and 3-aminopropanamide hydrochloride, respectively. The TFA salt of N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((2-(4-methyl-3-oxopiperazin-1-yl)ethyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide was isolated as an off-white solid. C20H22ClFN8O2. 461.2/463.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 11.36 (br. s, 1H), 8.95 (s, 1H), 7.97 (d, J = 6.2 Hz, 1H), 7.11 (t, J = 9.0 Hz, 1H), 7.02 (dd, J = 6.5, 2.7 Hz, 1H), 6.92 (d, J = 6.2 Hz, 1H), 6.59 (m, 1H), 3.80 - 3.60 (m, 3H), 3.45 - 3.35 (m, 3H), 3.25 - 3.05 (m, 2H), 3.05 - 2.90 (m, 2H), 2.85 (s, 3H). 19F NMR (377 MHz, DMSO-d6) δ -74.7 (9F), -126.7 (1F).
    • Example 502: N-(3-chloro-4-fluorophenyl)-2-((2-(3,3-difluoropiperidin-1-yl)ethyl)amino)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0912
  • Example 502 was made analogously to Example 229 using 3-(2-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one and 2-(3,3-difluoropiperidin-1-yl)ethan-1-amine in place of 3-(2-chloro-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one and 3-aminopropanamide hydrochloride, respectively. The TFA salt of N-(3-chloro-4-fluorophenyl)-2-((2-(3,3-difluoropiperidin-1-yl)ethyl)amino)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide was isolated as an off-white solid. C20H21ClF3N7O. 468.3/470.2 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 11.38 (s, 1H), 8.95 (s, 1H), 7.98 (d, J = 6.2 Hz, 1H), 7.11 (t, J = 9.0 Hz, 1H), 7.02 (dd, J = 6.5, 2.7 Hz, 1H), 6.93 (d, J = 6.2 Hz, 1H), 6.59 (ddd, J = 9.0, 4.1, 2.8 Hz, 1H), 3.66 (m, 2H), 3.10 (m, 2H), 2.90 (m, 2H), 2.75 (m, 2H), 1.97 (m, 2H), 1.77 (m, 2H). 19F NMR (377 MHz, DMSO-d6) δ -84.9 (9F), -108.4 (2F), -136.8 (1F).
    • Example 503: 2-((1-acetylpyrrolidin-3-yl)amino)-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0913
  • Example 503 was made analogously to Example 229 using 3-(2-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one and 1-(3-aminopyrrolidin-1-yl)ethan-1-one in place of 3-(2-chloro-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one and 3-aminopropanamide hydrochloride, respectively. The TFA salt of 2-((1-acetylpyrrolidin-3-yl)amino)-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide was isolated as an off-white solid. C19H19ClFN7O2. 432.4/434.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 11.40 (s, 1H), 8.96 (s, 1H), 7.98 (dd, J = 6.3, 4.2 Hz, 1H), 7.11 (t, J = 9.0 Hz, 1H), 7.04 (dd, J = 6.3, 2.6 Hz, 1H), 6.94 (dd, J = 7.9, 6.3 Hz, 1H), 6.60 (dt, J = 9.3, 3.3 Hz, 1H), 4.54 - 4.36 (m, 2H), 3.77 (m, 1H), 3.59 (m, 1H), 2.34-2.11 (m, 2H), 2.07 (m, 1H), 1.96 (d, J = 11.3 Hz, 3H). 19F NMR (376 MHz, DMSO-d6) δ -74.5, -126.5.
    • Example 504: N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((1-(methylsulfonyl)pyrrolidin-3-yl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0914
  • Example 504 was made analogously to Example 229 using 3-(2-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one and 1-(methylsulfonyl)pyrrolidin-3-amine in place of 3-(2-chloro-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one and 3-aminopropanamide hydrochloride, respectively. The TFA salt of N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((1-(methylsulfonyl)pyrrolidin-3-yl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide was isolated as an off-white solid. C18H19ClFN7O3S. 468.4/470.2 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 11.41 (s, 1H), 8.96 (s, 1H), 7.99 (d, J = 6.3 Hz, 1H), 7.10 (t, J = 9.0 Hz, 1H), 7.03 (dd, J = 6.5, 2.7 Hz, 1H), 6.95 (d, J = 6.3 Hz, 1H), 6.60 (ddd, J = 9.0, 4.1, 2.8 Hz, 1H), 4.55 - 4.42 (m, 2H), 3.59 (m, 1H), 3.27 (m, 1H), 2.95 (s, 3H), 2.37 - 2.21 (m, 2H), 2.05 (m, 1H). 19F NMR (376 MHz, DMSO-d6) δ -74.5, -126.5.
    • Example 505: N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((3-(methylsulfonyl)propyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0915
  • Example 505 was made analogously to Example 229 using 3-(2-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one and 3-(methylsulfonyl)propan-1-amine hydrochloride and N-ethyl-N-isopropylpropan-2-amine in place of 3-(2-chloro-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one and 3-aminopropanamide hydrochloride, respectively. The TFA salt of N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((3-(methylsulfonyl)propyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide was isolated as an off-white solid. C17H18ClFN6O3S. 441.3/443.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 11.39 (br. s, 1H), 8.95 (s, 1H), 7.97 (d, J = 6.3 Hz, 1H), 7.10 (t, J = 9.0 Hz, 1H), 7.04 (dd, J = 6.5, 2.7 Hz, 1H), 6.92 (d, J = 6.2 Hz, 1H), 6.59 (ddd, J = 9.0, 4.0, 2.7 Hz, 1H), 3.56 (m, 2H), 3.20 (m, 2H), 3.00 (s, 3H), 2.04 (p, J = 7.1 Hz, 2H). 19F NMR (377 MHz, DMSO-d6) δ -74.2 (6F), -126.3 (1F).
    • Example 506: N-(3-chloro-4-fluorophenyl)-2-(((1,1-dioxidotetrahydrothiophen-3-yl)methyl)amino)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0916
  • Example 506 was made analogously to Example 229 using 3-(2-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one and 3-(aminomethyl)tetrahydrothiophene 1,1-dioxide hydrochloride and N-ethyl-N-isopropylpropan-2-amine in place of 3-(2-chloro-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one and 3-aminopropanamide hydrochloride, respectively. The TFA salt of N-(3-chloro-4-fluorophenyl)-2-(((1,1-dioxidotetrahydrothiophen-3-yl)methyl)amino)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide was isolated as an off-white solid. C18H18ClFN6O3S. 453.3/455.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 8.95 (br. s, 1H), 7.97 (d, J = 6.3 Hz, 1H), 7.10 (t, J = 9.0 Hz, 1H), 7.03 (dd, J = 6.4, 2.7 Hz, 1H), 6.93 (d, J = 6.2 Hz, 1H), 6.59 (m, 1H), 3.56 (m, 2H), 3.24 (m, 2H), 3.08 (m, 1H), 2.91 (dd, J = 13.2, 9.5 Hz, 1H), 2.74 (d, J = 11.6 Hz, 1H), 2.25 (m, 1H), 1.86 (dq, J = 13.1, 9.3 Hz, 1H). 19F NMR (376 MHz, DMSO-d6) δ -74.4, -126.5.
    • Example 507: N-(3-chloro-4-fluorophenyl)-2-((3-((4-fluorophenyl)sulfonyl)propyl)amino)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0917
  • Example 507 was made analogously to Example 229 using 3-(2-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one and 3-((4-fluorophenyl)sulfonyl)propan-1-amine in place of 3-(2-chloro-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one and 3-aminopropanamide hydrochloride, respectively. The TFA salt of N-(3-chloro-4-fluorophenyl)-2-((3-((4-fluorophenyl)sulfonyl)propyl)amino)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide was isolated as an off-white solid. C22H19ClF2N6O3S. 521.4/523.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 11.38 (br. s, 1H), 8.94 (s, 1H), 7.97 (m, 3H), 7.51 (m, 2H), 7.10 (t, J = 9.0 Hz, 1H), 7.03 (dd, J = 6.5, 2.7 Hz, 1H), 6.92 (d, J = 6.3 Hz, 1H), 6.59 (dt, J = 9.0, 3.5 Hz, 1H), 3.50 (m, 2H), 3.43 (m, 2H), 1.89 (p, J = 7.1 Hz, 2H). 19F NMR (376 MHz, DMSO-d6) δ -74.4, -105.2,-126.5.
    • Example 508: (R)-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((1-(oxetan-3-yl)pyrrolidin-3-yl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
  • Figure imgb0918
  • Example 508 was made analogously to Example 229 using 3-(2-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one and (R)-1-(oxetan-3-yl)pyrrolidin-3-amine in place of 3-(2-chloro-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one and 3-aminopropanamide hydrochloride, respectively. The TFA salt of (R)-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((1-(oxetan-3-yl)pyrrolidin-3-yl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide was isolated as an off-white solid. C20H21ClFN7O2. 446.4/448.2 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 11.30 (br. s, 1H), 8.93 (s, 1H), 7.99 (d, J = 6.1 Hz, 1H), 7.09 (t, J = 9.0 Hz, 1H), 7.03 - 6.92 (m, 2H), 6.58 (ddd, J = 8.9, 4.0, 2.7 Hz, 1H), 4.78 (t, J = 7.4 Hz, 2H), 4.69 - 4.55 (m, 3H), 4.47 (m, 1H), 3.8 - 3.3 (m, 5H), 2.09 (d, J = 11.6 Hz, 1H). 19F NMR (376 MHz, DMSO-d6) δ -74.6, -126.7.
    • Biological Examples
  • Activity testing was conducted in the Examples below using methods described herein and those well known in the art.
    • Example 509. Cell-based (HeLa) Assay for Measurement of IDO1 Inhibition
  • To measure IDO1 inhibition in tissue culture, HeLa cells were treated with a test compound in the presence of IFNγ, which induces IDO1 expression. Following incubation, cell supernatants were assayed for kynurenine levels, an indicator of IDO1 activity.
  • H1-HeLa cells (ATCC #CRL-1958) were seeded in 384-well plates (Greiner #82051-282) at a volume of 50 µL/well in DMEM (Corning #15-018-CM) supplemented with 10% FBS (Corning #35-011-CV) and 1% P/S/G (Corning #30-009-CL) at a density of 1,250 cells/well and incubated overnight at 37°C, 5% CO2/100% humidity. The following day, the test compounds were added in DMSO (0.5% final) at various concentrations, and IDO1 was inducibly expressed by the addition of 50 uL/well of 50ng/mL of INFγ (Peprotech #300-02) in cell plating media. As a positive control, 50 uL of the cell plating media without IFNγ was added to several wells. Following a 48 hour incubation, the plates were spun down at 1,200 RPM for 5 min at 10 °C. 65 µL/well of the supernatant was then transferred to new 384-well plates (Thermo #262160) that contained 10 uL/well of 30% TCA (Sigma #TO699), and the plates were sealed and incubated at 60°C for 30 min. The plates were then centrifuged for 15 min at 2,000 RPM at 10 °C. 40 µL/well of the supernatant was transferred to new 384-well plates (Thermo #262160) and was reacted with 40 µL/well of 2% (w/v) p-dimethlyaminobenzaldehyde (Sigma #156417) in glacial acetic acid (Sigma #A6283). The reaction was incubated at room temperature for 10 min and absorbance at 480 nm was read using a PerkinElmer Envision plate reader.
  • Data in Table 1 were normalized based on positive (- IFNγ) and negative (+ IFNγ) controls and EC50 values were calculated from the fit of the dose-response curves to a four-parameter equation. All EC50 values represent geometric mean values of a minimum of four determinations. These assays generally produced results within 2-fold of the reported mean. Table 1
    Example No. Name EC50 (nM)
    1 N-(3-chloro-4-fluorophenyl)-N'-hydroxy-7-methyl-3H-benzimidazole-4-carboximidamide 1222
    2 N-(3-chloro-4-fluorophenyl)-N'-hydroxy-7-(trifluoromethoxy)-3H-benzimidazole-4-carboximidamide 2455
    3 N-(3-chloro-4-fluorophenyl)-5-fluoro-N'-hydroxy-3H-benzimidazole-4-carboximidamide 4801
    4 N-(3-chloro-4-fluorophenyl)-6-fluoro-N'-hydroxy-1H-benzimidazole-4-carboximidamide 527
    5 N-(3-chloro-4-fluorophenyl)-7-fluoro-N'-hydroxy-3H-benzimidazole-4-carboximidamide 542
    6 7-chloro-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-3H-benzimidazole-4-carboximidamide 793
    7 N-(3-chloro-4-fluorophenyl)-N'-hydroxy-7-(trifluoromethyl)-1H-benzimidazole-4-carboximidamide 926
    8 N-(3-chloro-4-fluorophenyl)-N'-hydroxy-3H-benzimidazole-4-carboximidamide 1792
    9 N-(3-chloro-4-fluorophenyl)-6-fluoro-N'-hydroxy-7-methyl-3H-benzimidazole-4-carboximidamide 634
    10 N-(3-chloro-4-fluorophenyl)-6,7-difluoro-N'-hydroxy-3H-benzimidazole-4-carboximidamide 438
    11 6-chloro-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-3H-benzimidazole-4-carboximidamide 7604
    12 7-bromo-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-3H-benzimidazole-4-carboximidamide 660
    13 2-amino-N-(3-chloro-4-fluorophenyl)-6,7-difluoro-N'-hydroxy-3H-benzimidazole-4-carboximidamide 2739
    14 2-amino-N-(3-bromo-4-fluorophenyl)-6,7-difluoro-N'-hydroxy-3H-benzimidazole-4-carboximidamide 494
    15 2-amino-N-(3-bromophenyl)-6,7-difluoro-N'-hydroxy-3H-benzimidazole-4-carboximidamide 570
    16 2-amino-N-(3-chlorophenyl)-6,7-difluoro-N'-hydroxy-3H-benzimidazole-4-carboximidamide 607
    17 2-amino-6,7-difluoro-N-[4-fluoro-3-(trifluoromethyl)phenyl]-N'-hydroxy-3H-benzimidazole-4-carboximidamide 1092
    18 2-amino-N-(3-bromophenyl)-7-fluoro-N'-hydroxy-3H-benzimidazole-4-carboximidamide 312
    19 2-amino-N-(3-bromo-4-fluorophenyl)-7-fluoro-N'-hydroxy-3H-benzimidazole-4-carboximidamide 456
    20 2-amino-N-(3-chlorophenyl)-7-fluoro-N'-hydroxy-3H-benzimidazole-4-carboximidamide 404
    21 2-amino-7-fluoro-N-[4-fluoro-3-(trifluoromethyl)phenyl]-N'-hydroxy-3H-benzimidazole-4-carboximidamide 725
    22 2-amino-N-(3-chloro-4-fluorophenyl)-7-fluoro-N'-hydroxy-3H-benzimidazole-4-carboximidamide 382
    23 N-(3-chloro-4-fluorophenyl)-6,7-difluoro-N'-hydroxy-2-(2-morpholin-4-ylethylamino)-3H-benzimidazole-4-carboximidamide 346
    24 N-(3-chlorophenyl)-4,5-difluoro-N'-hydroxy-2-(((3-methoxypropyl)amino)methyl)-1H-benzo[d]imidazole-7-carboximidamide 1923
    25 N-(3-chlorophenyl)-2-(((cyclopropylmethyl)amino)methyl)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide 1457
    26 N-(3-chlorophenyl)-2-((dimethylamino)methyl)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide 1212
    27 N-(3-chlorophenyl)-4,5-difluoro-N'-hydroxy-2-((isopropylamino)methyl)-1H-benzo[d]imidazole-7-carboximidamide 839
    28 N-(3-chlorophenyl)-2-((ethylamino)methyl)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide 801
    29 N-(3-chlorophenyl)-4,5-difluoro-N'-hydroxy-2-(hydroxymethyl)-1H-benzo[d]imidazole-7-carboximidamide 1541
    30 N-(3-chlorophenyl)-4,5-difluoro-N'-hydroxy-2-((methylamino)methyl)-1H-benzo[d]imidazole-7-carboximidamide 1106
    31 2-(aminomethyl)-N-(3-chlorophenyl)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide 1680
    32 N-(3-chloro-4-fluorophenyl)-6,7-difluoro-N'-hydroxy-2-morpholin-4-yl-3H-benzimidazole-4-carboximidamide 9276
    33 N-(3-chloro-4-fluorophenyl)-7-fluoro-N'-hydroxy-2-(2-methylsulfonylethylamino)-3H-benzimidazole-4-carboximidamide 1833
    34 N-(3-Chloro-4-fluorophenyl)-4-fluoro-N'-hydroxy-2-((2-morpholinoethyl)amino)-1H-benzo[d]imidazole-7-carboximidamide 6739
    35 N-(3-chloro-4-fluorophenyl)-6,7-difluoro-N'-hydroxy-2-(2-methylsulfonylethylamino)-3H-benzimidazole-4-carboximidamide 2153
    36 N-(3-chloro-4-fluorophenyl)-2-[2-(4,4-difluoropiperidin-1-yl)ethylamino]-6,7-difluoro-N'-hydroxy-3H-benzimidazole-4-carboximidamide 712
    37 N-(3-chloro-4-fluorophenyl)-6,7-difluoro-N'-hydroxy-2-(1-morpholin-4-ylpropan-2-ylamino)-3H-benzimidazole-4-carboximidamide 514
    38 N-(3-chloro-4-fluorophenyl)-6,7-difluoro-N'-hydroxy-2-(methylamino)-3H-benzimidazole-4-carboximidamide 607
    39 N-(3-chloro-4-fluorophenyl)-2-[3-(dimethylamino)propylamino]-6,7-difluoro-N'-hydroxy-3H-benzimidazole-4-carboximidamide 473
    40 N-(3-chloro-4-fluorophenyl)-6,7-difluoro-N'-hydroxy-2-(2-methoxyethylamino)-3H-benzimidazole-4-carboximidamide 1523
    41 N-(3-chloro-4-fluorophenyl)-6,7-difluoro-N'-hydroxy-2-(2-pyrrolidin-1-ylethylamino)-3H-benzimidazole-4-carboximidamide 240
    42 N-(3-chloro-4-fluorophenyl)-2-[2-(diethylamino)ethylamino]-6,7-difluoro-N'-hydroxy-3H-benzimidazole-4-carboximidamide 247
    43 N-(3-chloro-4-fluorophenyl)-2-[2-(dimethylamino)ethylamino]-6,7-difluoro-N'-hydroxy-3H-benzimidazole-4-carboximidamide 136
    44 N-(3-chlorophenyl)-6,7-difluoro-N'-hydroxy-2-(1-methylpiperidin-3-yl)-3H-benzimidazole-4-carboximidamide 1645
    45 N-(3-chloro-4-fluorophenyl)-6,7-difluoro-N'-hydroxy-2-[(3-methoxypropylamino)methyl]-1H-benzimidazole-4-carboximidamide 1324
    46 N-(3-chloro-4-fluorophenyl)-6,7-difluoro-N'-hydroxy-2-(hydroxymethyl)-3H-benzimidazole-4-carboximidamide 835
    47 2-(aminomethyl)-N-(3-chloro-4-fluorophenyl)-6,7-difluoro-N'-hydroxy-1H-benzimidazole-4-carboximidamide 1075
    48 N-(3-chloro-4-fluorophenyl)-6,7-difluoro-N'-hydroxy-2-(methylaminomethyl)-1H-benzimidazole-4-carboximidamide 434
    49 N-(3-chloro-4-fluorophenyl)-2-[(cyclopropylmethylamino)methyl]-6,7-difluoro-N'-hydroxy-1H-benzimidazole-4-carboximidamide 1057
    50 N-(3-chloro-4-fluorophenyl)-2-(ethylaminomethyl)-6,7-difluoro-N'-hydroxy-1H-benzimidazole-4-carboximidamide 457
    51 N-(3-chloro-4-fluorophenyl)-6,7-difluoro-N'-hydroxy-2-[(propan-2-ylamino)methyl]-1H-benzimidazole-4-carboximidamide 566
    52 N-(3-chloro-4-fluorophenyl)-2-[(dimethylamino)methyl]-6,7-difluoro-N'-hydroxy-1H-benzimidazole-4-carboximidamide 526
    53 N-(3-chloro-4-fluorophenyl)-2-[2-(dimethylamino)ethyl]-6,7-difluoro-N'-hydroxy-1H-benzimidazole-4-carboximidamide 916
    54 N-(3-bromo-4-fluorophenyl)-2-[2-(dimethylamino)ethyl]-6,7-difluoro-N'-hydroxy-1H-benzimidazole-4-carboximidamide 461
    55 N-(3-bromophenyl)-2-[2-(dimethylamino)ethyl]-6,7-difluoro-N'-hydroxy-1H-benzimidazole-4-carboximidamide 379
    56 N-(3-chlorophenyl)-2-[2-(dimethylamino)ethyl]-6,7-difluoro-N'-hydroxy-1H-benzimidazole-4-carboximidamide 562
    57 N-(3-chloro-4-fluorophenyl)-6,7-difluoro-N'-hydroxy-2-[2-(methylamino)ethyl]-1H-benzimidazole-4-carboximidamide 1093
    58 N-(3-chloro-4-fluorophenyl)-2-[2-(diethylamino)ethyl]-6,7-difluoro-N'-hydroxy-1H-benzimidazole-4-carboximidamide 786
    59 N-(3-chloro-4-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide 208
    60 N-(5-chloro-2-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide 322
    61 N-(5-bromo-2,4-difluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide 371
    62 N-(5-chloro-2,4-difluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide 385
    63 N-(3,5-dichloro-4-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide 774
    64 N-(3-chloro-2,4-difluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide 813
    65 N-(3-cyclopropyl-4-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide 1809
    66 N'-hydroxy-N-[4-(trifluoromethoxy)phenyl]-1H-imidazo[4,5-b]pyridine-7-carboximidamide 4871
    67 N-(1-benzofuran-4-yl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide 583
    68 N-(1-benzofuran-6-yl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide 890
    69 N-(1-benzofuran-7-yl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide 1339
    70 N-(1-benzofuran-5-yl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide 1479
    71 N-(5-bromo-2-fluorophenyl)-N'-hydroxy-3H-imidazo[4,5-b]pyridine-7-carboximidamide 207
    72 N-(3-bromo-5-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide 280
    73 N'-hydroxy-N-[3-(trifluoromethyl)phenyl]-1H-imidazo[4,5-b]pyridine-7-carboximidamide 373
    74 N-(2,2-difluoro-1,3-benzodioxol-5-yl)-N'-hydroxy-3H-imidazo[4,5-b]pyridine-7-carboximidamide 923
    75 N-[3-fluoro-5-(trifluoromethyl)phenyl]-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide 2109
    76 N-(2,5-dichlorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide 769
    77 N-(4-fluoro-3-phenylphenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide 2289
    78 N-(3-but-1-ynyl-4-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide 2641
    79 N-[3-(2-cyclopropylethynyl)-4-fluorophenyl]-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide 3223
    80 N-(3-bromophenyl)-N'-hydroxy-3H-imidazo[4,5-b]pyridine-7-carboximidamide 111
    81 N-(3-bromo-4-fluorophenyl)-N'-hydroxy-3H-imidazo[4,5-b]pyridine-7-carboximidamide 140
    82 N-(3-chlorophenyl)-N'-hydroxy-3H-imidazo[4,5-b]pyridine-7-carboximidamide 160
    83 N-[4-fluoro-3-(trifluoromethyl)phenyl]-N'-hydroxy-3H-imidazo[4,5-b]pyridine-7-carboximidamide 315
    84 N-(4-fluoro-3-prop-1-ynylphenyl)-N'-hydroxy-3H-imidazo[4,5-b]pyridine-7-carboximidamide 445
    85 N-(3-bromo-4-chlorophenyl)-N'-hydroxy-3H-imidazo[4,5-b]pyridine-7-carboximidamide 462
    86 N-(3,4-dichlorophenyl)-N'-hydroxy-3H-imidazo[4,5-b]pyridine-7-carboximidamide 639
    87 N-(4-chlorophenyl)-N'-hydroxy-3H-imidazo[4,5-b]pyridine-7-carboximidamide 846
    88 N-(4-bromophenyl)-N'-hydroxy-3H-imidazo[4,5-b]pyridine-7-carboximidamide 916
    89 N-(4-fluorophenyl)-N'-hydroxy-3H-imidazo[4,5-b]pyridine-7-carboximidamide 943
    90 N-(3-cyano-4-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide 1047
    91 N'-hydroxy-N-[4-(trifluoromethyl)phenyl]-3H-imidazo[4,5-b]pyridine-7-carboximidamide 2240
    92 N'-hydroxy-N-(3-methoxyphenyl)-3H-imidazo[4,5-b]pyridine-7-carboximidamide 3892
    93 N-(4-fluoro-3-propan-2-ylphenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide 5096
    94 N'-hydroxy-N-(4-methylphenyl)-3H-imidazo[4,5-b]pyridine-7-carboximidamide 6350
    95 N-(3-ethynylphenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide 302
    96 N-(3-ethylphenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide 803
    97 N-(3-ethynyl-4-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide 380
    98 N-[3-(difluoromethyl)phenyl]-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide 550
    99 N'-hydroxy-N-[3-(trifluoromethoxy)phenyl]-1H-imidazo[4,5-b]pyridine-7-carboximidamide 602
    100 N'-hydroxy-N-phenyl-1H-imidazo[4,5-b]pyridine-7-carboximidamide 770
    101 N-[4-fluoro-3-(trifluoromethoxy)phenyl]-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide 845
    102 N'-hydroxy-N-naphthalen-2-yl-1H-imidazo[4,5-b]pyridine-7-carboximidamide 1928
    103 N-(3-chloronaphthalen-2-yl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide 8075
    104 N'-hydroxy-N-naphthalen-1-yl-1H-imidazo[4,5-b]pyridine-7-carboximidamide 1966
    105 N-(4-chloronaphthalen-1-yl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide 3032
    106 N-(4-fluoro-3-methoxyphenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide 5536
    107 N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-methyl-1H-imidazo[4,5-b]pyridine-7-carboximidamide 1925
    108 N-(3-chloro-4-fluorophenyl)-2-ethyl-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide 3192
    109 N-(3-chloro-4-fluorophenyl)-2-cyclopropyl-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide 1386
    110 N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(methoxymethyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide 2320
    111 4-(3-chloro-4-fluorophenyl)-3-[2-(hydroxymethyl)-1H-imidazo[4,5-b]pyridin-7-yl]-1,2,4-oxadiazol-5-one 4452
    112 N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(morpholin-4-ylmethyl)-3H-imidazo[4,5-b]pyridine-7-carboximidamide 9531
    113 N-(3-chloro-4-fluorophenyl)-2-[(dimethylamino)methyl]-N'-hydroxy-3H-imidazo[4,5-b]pyridine-7-carboximidamide 1837
    114 N-(3-chloro-4-fluorophenyl)-2-(ethylaminomethyl)-N'-hydroxy-3H-imidazo[4,5-b]pyridine-7-carboximidamide 927
    115 2-[(benzylamino)methyl]-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-3H-imidazo[4,5-b]pyridine-7-carboximidamide 1761
    116 N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-[(propan-2-ylamino)methyl]-3H-imidazo[4,5-b]pyridine-7-carboximidamide 740
    117 N-(3-chloro-4-fluorophenyl)-2-[(cyclopropylmethylamino)methyl]-N'-hydroxy-3H-imidazo[4,5-b]pyridine-7-carboximidamide 765
    118 N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-[(2,2,2-trifluoroethylamino)methyl]-3H-imidazo[4,5-b]pyridine-7-carboximidamide 4644
    119 N-(3-chloro-4-fluorophenyl)-2-[(cyclopropylamino)methyl]-N'-hydroxy-3H-imidazo[4,5-b]pyridine-7-carboximidamide 2150
    120 N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-[(3-methoxypropylamino)methyl]-3H-imidazo[4,5-b]pyridine-7-carboximidamide 1334
    121 N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-[(pyridin-2-ylmethylamino)methyl]-3H-imidazo[4,5-b]pyridine-7-carboximidamide 1373
    122 N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-[[3-methoxypropyl(methyl)amino]methyl]-1H-imidazo[4,5-b]pyridine-7-carboximidamide 1883
    123 N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-[[(2-methoxyphenyl)methylamino]methyl]-1H-imidazo[4,5-b]pyridine-7-carboximidamide 1909
    124 N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-[(2-methoxyethylamino)methyl]-3H-imidazo[4,5-b]pyridine-7-carboximidamide 2059
    125 N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-[(2-pyridin-2-ylethylamino)methyl]-3H-imidazo[4,5-b]pyridine-7-carboximidamide 2083
    126 N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-[(pyridin-3-ylmethylamino)methyl]-3H-imidazo[4,5-b]pyridine-7-carboximidamide 2280
    127 N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-[(oxan-2-ylmethylamino)methyl]-1H-imidazo[4,5-b]pyridine-7-carboximidamide 2364
    128 2-(anilinomethyl)-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-3H-imidazo[4,5-b]pyridine-7-carboximidamide 2399
    129 N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-[(oxan-3-ylmethylamino)methyl]-1H-imidazo[4,5-b]pyridine-7-carboximidamide 2575
    130 N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-[(pyrimidin-2-ylmethylamino)methyl]-3H-imidazo[4,5-b]pyridine-7-carboximidamide 2815
    131 N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-[(3-morpholin-4-ylpropylamino)methyl]-3H-imidazo[4,5-b]pyridine-7-carboximidamide 3016
    132 N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-[(oxan-4-ylamino)methyl]-1H-imidazo[4,5-b]pyridine-7-carboximidamide 3433
    133 N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-[(pyridin-4-ylmethylamino)methyl]-3H-imidazo[4,5-b]pyridine-7-carboximidamide 3711
    134 N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-[(pyrazin-2-ylmethylamino)methyl]-1H-imidazo[4,5-b]pyridine-7-carboximidamide 3988
    135 N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-[(oxolan-3-ylmethylamino)methyl]-1H-imidazo[4,5-b]pyridine-7-carboximidamide 5105
    136 N-(3-chloro-4-fluorophenyl)-2-[[2-(dimethylamino)ethylamino]methyl]-N'-hydroxy-3H-imidazo[4,5-b]pyridine-7-carboximidamide 6274
    137 N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-[(2-pyrimidin-2-ylethylamino)methyl]-3H-imidazo[4,5-b]pyridine-7-carboximidamide 7492
    138 N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-[(3-hydroxypropylamino)methyl]-1H-imidazo[4,5-b]pyridine-7-carboximidamide 8239
    139 N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(pyrrolidin-1-ylmethyl)-3H-imidazo[4,5-b]pyridine-7-carboximidamide 1400
    140 N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(piperidin-1-ylmethyl)-3H-imidazo[4,5-b]pyridine-7-carboximidamide 1609
    141 N-(3-chloro-4-fluorophenyl)-2-[(2,2-dimethylpropylamino)methyl]-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide 1677
    142 N-(3-chloro-4-fluorophenyl)-2-[(2,2-difluoroethylamino)methyl]-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide 5155
    143 N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-[[(3-hydroxy-2,2-dimethylpropyl)amino]methyl]-1H-imidazo[4,5-b]pyridine-7-carboximidamide 7346
    144 N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-[(1,3-thiazol-2-ylmethylamino)methyl]-1H-imidazo[4,5-b]pyridine-7-carboximidamide 8228
    145 N-[[7-[(Z)-N-(3-chloro-4-fluorophenyl)-N'-hydroxycarbamimidoyl]-3H-imidazo[4,5-b]pyridin-2-yl]methyl] acetamide 9760
    146 N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-thiophen-2-yl-3H-imidazo[4,5-b]pyridine-7-carboximidamide 4215
    147 N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-pyridin-3-yl-1H-imidazo[4,5-b]pyridine-7-carboximidamide 1935
    148 N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(1H-pyrrol-2-yl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide 2229
    149 N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(1H-imidazol-2-yl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide 529
    150 N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(1H-pyrazol-5-yl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide 8480
    151 N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(5-methyl-1H-imidazol-2-yl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide 463
    152 N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-[(2S)-pyrrolidin-2-yl]-1H-imidazo[4,5-b]pyridine-7-carboximidamide 4036
    153 2-amino-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide 897
    154 N-(3-chloro-4-fluorophenyl)-2-(cyclopropylamino)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide 529
    155 2-anilino-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide 2146
    156 N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(2-phenylethylamino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide 769
    157 N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(2,2,2-trifluoroethylamino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide 1088
    158 N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(methylamino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide 460
    159 propan-2-yl N-[7-[(Z)-N-(3-chloro-4-fluorophenyl)-N'-hydroxycarbamimidoyl]-1H-imidazo[4,5-b]pyridin-2-yl]carbamate 453
    160 ethyl N-[7-[(Z)-N-(3-chloro-4-fluorophenyl)-N'-hydroxycarbamimidoyl]-1H-imidazo[4,5-b]pyridin-2-yl]carbamate 423
    161 N-(3-chloro-4-fluorophenyl)-2-(cyclopropylmethylamino)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide 655
    162 N-(3-chloro-4-fluorophenyl)-2-[(3,3-difluorocyclobutyl)amino]-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide 4017
    163 N-(3-chloro-4-fluorophenyl)-2-(ethylamino)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide 1084
    164 N-(3-chloro-4-fluorophenyl)-2-(cyclobutylamino)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide 798
    165 N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(propan-2-ylamino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide 705
    166 N-(3-chlorophenyl)-N'-hydroxy-2-(methylamino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide 383
    167 N-(3-chloro-4-fluorophenyl)-2-[2-(diethylamino)ethylamino]-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide 2912
    168 N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(2-morpholin-4-ylethylamino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide 1158
    169 N-(3-chloro-4-fluorophenyl)-2-(dimethylamino)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide 6269
    170 2-(chloromethyl)-N-[4-fluoro-3-(trifluoromethyl)phenyl]-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide 1936
    171 N-[4-fluoro-3-(trifluoromethyl)phenyl]-N'-hydroxy-2-(hydroxymethyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide 4000
    172 N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(1-hydroxyethyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide 3858
    173 N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-[hydroxy(phenyl)methyl]-1H-imidazo[4,5-b]pyridine-7-carboximidamide 9700
    174 N-(3-chloro-4-fluorophenyl)-2-[cyclopropyl(hydroxy)methyl]-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide 7086
    175 N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(2-hydroxypropan-2-yl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide 6417
    176 N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(2,2,2-trifluoro-1-hydroxyethyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide 4201
    177 N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(hydroxymethyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide 1674
    178 N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(methylaminomethyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide 1477
    179 2-(aminomethyl)-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide 7664
    180 2-(benzenesulfonamidomethyl)-N-(3 -chloro-4-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide 1406
    181 N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(methanesulfonamidomethyl)-3H-imidazo[4,5-b]pyridine-7-carboximidamide 8969
    182 N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-[(pyrimidin-2-ylamino)methyl]-3H-imidazo[4,5-b]pyridine-7-carboximidamide 6401
    183 N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(2-hydroxyethyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide 2401
    184 N-(3-chloro-4-fluorophenyl)-2-[2-(dimethylamino)ethyl]-N'-hydroxy-3H-imidazo[4,5-b]pyridine-7-carboximidamide 593
    185 N-(3-chloro-4-fluorophenyl)-2-[2-(diethylamino)ethyl]-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide 531
    186 N-(3-chloro-4-fluorophenyl)-2-[2-[cyclopropylmethyl(methyl)amino] ethyl]-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide 565
    187 N-(3-chloro-4-fluorophenyl)-2-[2-[2,2-difluoroethyl(methyl)amino]ethyl]-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide 3405
    188 N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-[2-(methylamino)ethyl]-3H-imidazo[4,5-b]pyridine-7-carboximidamide 1513
    189 2-(2-aminoethyl)-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-3H-imidazo[4,5-b]pyridine-7-carboximidamide 1777
    190 N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-(2-((2-methoxyethyl)amino)ethyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide 1513
    191 N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(2-morpholin-4-ylethyl)-3H-imidazo[4,5-b]pyridine-7-carboximidamide 2824
    192 N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(2-piperidin-1-ylethyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide 241
    193 N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(2-pyrrolidin-1-ylethyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide 358
    194 N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-[2-[2-methoxyethyl(methyl)amino]ethyl]-1H-imidazo[4,5-b]pyridine-7-carboximidamide 504
    195 N-(3-chloro-4-fluorophenyl)-2-[2-(dimethylamino)-1-hydroxyethyl]-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide 1158
    196 N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-[(2-methylpropylamino)methyl]-1H-imidazo[4,5-b]pyridine-7-carboximidamide 1330
    197 N-(3-chloro-4-fluorophenyl)-N'-hydroxy-3-methylimidazo[4,5-b]pyridine-7-carboximidamide 5456
    198 N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-[2-(2-methoxyethylamino)ethyl]-3H-imidazo[4,5-b]pyridine-7-carboximidamide 2339
    199 N-(3-chloro-4-fluorophenyl)-2-[3-(dimethylamino)propyl]-6,7-difluoro-N'-hydroxy-3H-benzimidazole-4-carboximidamide 4488
    200 N-(3-chloro-4-fluorophenyl)-7-fluoro-N'-hydroxy-2-(3-morpholin-4-ylpropylamino)-3H-benzimidazole-4-carboximidamide 564
    201 N-(3-chloro-4-fluorophenyl)-2-[2-(dimethylamino)ethylamino]-7-fluoro-N'-hydroxy-3H-benzimidazole-4-carboximidamide 428
    202 N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-[(1-methylpiperidin-2-yl)methylamino]-1H-imidazo[4,5-b]pyridine-7-carboximidamide 2090
    203 N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-[(1-methylpyrrolidin-3-yl)amino]-1H-imidazo[4,5-b]pyridine-7-carboximidamide 1344
    204 N-(3-chloro-4-fluorophenyl)-2-(2-(ethylamino)ethyl)-N'-hydroxy-3H-imidazo[4,5-b]pyridine-7-carboximidamide 2195
    205 N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(2-(isopropylamino)ethyl)-3H-imidazo[4,5-b]pyridine-7-carboximidamide 2823
    206 N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(2-(isobutylamino)ethyl)-3H-imidazo[4,5-b]pyridine-7-carboximidamide 2295
    207 N-(3-chloro-4-fluorophenyl)-2-(2-(cyclopropylamino)ethyl)-N'-hydroxy-3H-imidazo[4,5-b]pyridine-7-carboximidamide 1257
    209 2-(2-(2-amino-4,5-dihydro-1H-imidazol-1-yl)ethyl)-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide 5000
    210 N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-(2-(methylsulfonamido)ethyl)-1H-benzo[d]imidazole-7-carboximidamide >10000
    211 2-(2-aminoethyl)-N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide >10000
    212 N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((2-methoxyethyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide 876
    213 tert-butyl (2-(7-(N-(3-chloro-4-fluorophenyl)-N'-hydroxycarbamimidoyl)-4,5-difluoro-1H-benzo[d]imidazol-2-yl)ethyl)carbamate 3623
    214 N-(3-chloro-4-fluorophenyl)-2-((2-(4,4-difluoropiperidin-1-yl)ethyl)amino)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide 1908
    215 N-(3-chloro-4-fluorophenyl)-2-((2-(dimethylamino)ethyl)amino)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide 1195
    216 N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((2-(methylamino)ethyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide 2009
    217 N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((1-methylazepan-3-yl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide 2870
    218 N-(3-chloro-4-fluorophenyl)-2-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide >10000
    219 N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((2-((2-methoxyethyl)(methyl)amino)ethyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide 3829
    220 N-(3-chloro-4-fluorophenyl)-2-((2-((2,2-difluoroethyl)(methyl)amino)ethyl)amino)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide 2383
    221 N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((3-morpholinopropyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide 899
    222 N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((2-(piperidin-1-yl)ethyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide 1521
    223 N-(3-chloro-4-fluorophenyl)-2-((2-cyclohexylethyl)amino)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide 2182
    224 N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((2-(tetrahydro-2H-pyran-4-yl)ethyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide 3735
    225 N-(3-chloro-4-fluorophenyl)-2-((2,2-difluoroethyl)amino)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide 2190
    226 N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(oxetan-3-ylamino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide >10000
    227 N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((tetrahydrofuran-3-yl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide 2195
    228 N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((tetrahydro-2H-pyran-4-yl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide 2135
    229 3-((7-(N-(3-chloro-4-fluorophenyl)-N'-hydroxycarbamimidoyl)-4,5-difluoro-1H-benzo[d]imidazol-2-yl)amino)propanamide >10000
    230 N-(3-chloro-4-fluorophenyl)-2-((2-((2,2-difluoroethyl)amino)ethyl)amino)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide 3836
    231 N-(3-chloro-4-fluorophenyl)-2-((2-(cyclopropyl(methyl)amino)ethyl)amino)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide 291
    232 N-(3-chloro-4-fluorophenyl)-2-((2-(cyclopropyl(2-methoxyethyl)amino)ethyl)amino)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide 460
    233 2-((2-(azetidin-1-yl)ethyl)amino)-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide 1122
    234 N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((3-methoxypropyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide 698
    235 N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((2-(2-oxopyrrolidin-1-yl)ethyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide 4818
    236 N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((2-(morpholinosulfonyl)ethyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide 4765
    237 N-(3-chloro-4-fluorophenyl)-2-((2-(3-fluoropiperidin-1-yl)ethyl)amino)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide 442
    238 N-(3-bromo-4-fluorophenyl)-N'-hydroxy-2-((2-morpholinoethyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide 853
    239 N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((2-(methyl(tetrahydro-2H-pyran-4-yl)amino)ethyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide 1212
    240 N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((2-(isopropyl(methyl)amino)ethyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide 590
    241 2-(((1-aminocyclopropyl)methyl)amino)-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide 1374
    257 N-(3-bromo-4-fluorophenyl)-N'-hydroxy-2-(methylamino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide 241
    242 2-((2-(1-aminocyclopropyl)ethyl)amino)-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide 1626
    258 2-(2-(azepan-1-yl)ethyl)-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide 844
    259 2-(2-(azetidin-1-yl)ethyl)-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide 1299
    260 (R)-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(2-(3-hydroxypyrrolidin-1-yl)ethyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide 3205
    261 (S)-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(2-(3-hydroxypyrrolidin-1-yl)ethyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide 3453
    262 N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(2-(4-hydroxypiperidin-1-yl)ethyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide 3238
    263 N-(3-bromo-4-fluorophenyl)-2-(2-(dimethylamino)ethyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide 559
    264 N-(3-chlorophenyl)-2-(2-(dimethylamino)ethyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide 722
    265 N-(3-bromophenyl)-2-(2-(dimethylamino)ethyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide 501
    266 N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(2-(methylsulfonamido)ethyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide >10000
    267 N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(2-(sulfamoylamino)ethyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide >10000
    268 N-(3-chlorophenyl)-N'-hydroxy-2-(2-(pyrrolidin-1-yl)ethyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide 952
    269 N-(3-bromophenyl)-N'-hydroxy-2-(2-(pyrrolidin-1-yl)ethyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide 979
    270 N-(2-(7-(N-(3-chloro-4-fluorophenyl)-N'-hydroxycarbamimidoyl)-1H-imidazo[4,5-b]pyridin-2-yl)ethyl)acetamide >10000
    271 N-(3-chlorophenyl)-N'-hydroxy-2-(2-(piperidin-1-yl)ethyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide 602
    272 N-(3-bromophenyl)-N'-hydroxy-2-(2-(piperidin-1-yl)ethyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide 477
    273 Methyl (2-(7-(N-(3-chloro-4-fluorophenyl)-N'-hydroxycarbamimidoyl)-1H-imidazo[4,5-b]pyridin-2-yl)ethyl)carbamate >10000
    274 N-(3-chloro-4-fluorophenyl)-2-(2-((2,4-dimethoxybenzyl)amino)ethyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide 1966
    275 2-(2-(4-benzylpiperidin-1-yl)ethyl)-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide 675
    276 2-(2-(3-azabicyclo[3.3.1]nonan-3-yl)ethyl)-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide 618
    277 2-(2-(3-azabicyclo[3.2.1]octan-3-yl)ethyl)-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide 576
    278 N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((1-methylpiperidin-3-yl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide 1073
    279 (S)-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((2-(3-hydroxypyrrolidin-1-yl)ethyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide 5279
    280 (S)-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(3-hydroxypyrrolidin-1-yl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide >10000
    281 N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((1-(2-methoxyethyl)pyrrolidin-3-yl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide 1257
    282 N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(((4-methylmorpholin-3-yl)methyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide >10000
    283 N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((2-(pyrrolidin-1-yl)ethyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide 2719
    287 N-(3-chloro-4-fluorophenyl)-2-((ethylamino)methyl)-4-fluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide 1669
    288 N-(3-chloro-4-fluorophenyl)-2-((dimethylamino)methyl)-4-fluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide 1816
    289 -(3-chloro-4-fluorophenyl)-4-fluoro-N'-hydroxy-2-((isopropylamino)methyl)-1H-benzo[d]imidazole-7-carboximidamide 2232
    290 N-(3-chloro-4-fluorophenyl)-4-fluoro-N'-hydroxy-2-((methylamino)methyl)-1H-benzo[d]imidazole-7-carboximidamide 1292
    291 2-(aminomethyl)-N-(3-chloro-4-fluorophenyl)-4-fluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide 2647
    292 N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((2-hydroxy-2-methylpropyl)amino)-1H-benzo[d]imidazole-7-carboximidamide 3317
    293 N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((2-hydroxypropyl)amino)-1H-benzo[d]imidazole-7-carboximidamide 3003
    294 2-((7-(N-(3-chloro-4-fluorophenyl)-N'-hydroxycarbamimidoyl)-4,5-difluoro-1H-benzo[d]imidazol-2-yl)amino)acetamide 9954
    295 N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((2-hydroxyethyl)amino)-1H-benzo[d]imidazole-7-carboximidamide 3264
    296 N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((3-hydroxycyclobutyl)amino)-1H-benzo[d]imidazole-7-carboximidamide >10000
    297 N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((3-(pyridin-2-ylamino)propyl)amino)-1H-benzo[d]imidazole-7-carboximidamide 1153
    298 N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((2-sulfamoylethyl)amino)-1H-benzo[d]imidazole-7-carboximidamide 9558
    299 N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-(((1-methyl-1H-pyrazol-5-yl)methyl)amino)-1H-benzo[d]imidazole-7-carboximidamide 3443
    300 2-((2-(1H-pyrazol-1-yl)ethyl)amino)-N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide 3572
    301 2-((7-(N-(3-chloro-4-fluorophenyl)-N'-hydroxycarbamimidoyl)-4,5-difluoro-1H-benzo[d]imidazol-2-yl)amino)-N,N-dimethylacetamide 3960
    302 N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-(2-hydroxy-2-methylpropyl)-1H-benzo[d]imidazole-7-carboximidamide >10000
    303 N-(3-chloro-4-fluorophenyl)-2-((4-(dimethylamino)butyl)amino)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide 2935
    304 N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((piperidin-3-ylmethyl)amino)-1H-benzo[d]imidazole-7-carboximidamide >10000
    305 N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((1-methylpiperidin-2-yl)methyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide 3494
    306 N-(3-bromophenyl)-N'-hydroxy-2-((2-morpholinoethyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide 681
    307 N-(3-chloro-4-fluorophenyl)-5-fluoro-N'-hydroxy-4-methoxy-1H-benzo[d]imidazole-7-carboximidamide 209
    325 N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(piperidin-2-ylmethyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide >10000
    326 N-(3-chloro-4-fluorophenyl)-2-(1-(dimethylamino)propan-2-yl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide 4054
    327 N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(2-(methylamino)propyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide 7619
    328 N-(3-chloro-4-fluorophenyl)-2-(2-(dimethylamino)propyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide 3242
    329 N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(pyrrolidin-2-ylmethyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide 5000
    330 N-(3-chlorophenyl)-4,5-difluoro-N'-hydroxy-2-((2-(pyrrolidin-1-yl)ethyl)amino)-1H-benzo[d]imidazole-7-carboximidamide 414
    331 N-(3-bromophenyl)-4,5-difluoro-N'-hydroxy-2-((2-(pyrrolidin-1-yl)ethyl)amino)-1H-benzo[d]imidazole-7-carboximidamide 692
    333 2-((2-aminoethyl)amino)-N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide 1386
    334 N-(2-((7-(N-(3-chloro-4-fluorophenyl)-N'-hydroxycarbamimidoyl)-4,5-difluoro-1H-benzo[d]imidazol-2-yl)amino)ethyl)acetamide 6119
    335 N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((2-(methylsulfonamido)ethyl)amino)-1H-benzo[d]imidazole-7-carboximidamide >10000
    336 N-(3-chloro-4-fluorophenyl)-2-((2-(cyclopropanesulfonamido)ethyl)amino)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide >10000
    337 Methyl (2-((7-(N-(3-chloro-4-fluorophenyl)-N'-hydroxycarbamimidoyl)-4,5-difluoro-1H-benzo[d]imidazol-2-yl)amino)ethyl)carbamate 4405
    338 N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((2-(sulfamoylamino)ethyl)amino)-1H-benzo[d]imidazole-7-carboximidamide >10000
    339 N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((2-(phenylsulfonamido)ethyl)amino)-1H-benzo[d]imidazole-7-carboximidamide >10000
    340 N-(3-chloro-4-fluorophenyl)-2-((2-cyanoethyl)amino)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide 1781
    341 N-(3-chloro-4-fluorophenyl)-2-((2-(3-ethylureido)ethyl)amino)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide >10000
    342 N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((pyridin-2-ylmethyl)amino)-1H-benzo[d]imidazole-7-carboximidamide 8493
    343 N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((pyridin-3-ylmethyl)amino)-1H-benzo[d]imidazole-7-carboximidamide 3857
    344 N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((pyridin-3-ylmethyl)amino)-1H-benzo[d]imidazole-7-carboximidamide 3058
    345 2-(((1H-imidazol-2-yl)methyl)amino)-N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide 3843
    346 2-chloro-N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide 8468
    347 2-((2-aminobenzyl)amino)-N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide 3269
    348 N-(3-chloro-4-fluorophenyl)-2-((2-(dimethylamino)benzyl)amino)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide 3431
    349 N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-(((1-methyl-1H-imidazol-2-yl)methyl)amino)-1H-benzo[d]imidazole-7-carboximidamide 2544
    350 N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((pyrimidin-2-ylmethyl)amino)-1H-benzo[d]imidazole-7-carboximidamide 7031
    351 N-(3-chloro-4-fluorophenyl)-2-((3-(dimethylamino)-2,2-dimethylpropyl)amino)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide 432
    352 N-(3-chloro-4-fluorophenyl)-2-((3-(dimethylamino)-2-methylpropyl)amino)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide 437
    353 N-(3-chloro-4-fluorophenyl)-2-((3-(dimethylamino)butyl)amino)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide 1295
    354 N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((2-(1-methylpyrrolidin-2-yl)ethyl)amino)-1H-benzo[d]imidazole-7-carboximidamide 1207
    355 N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((2-(1-methylpiperidin-2-yl)ethyl)amino)-1H-benzo[d]imidazole-7-carboximidamide 2021
    356 N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-(((4-methylmorpholin-2-yl)methyl)amino)-1H-benzo[d]imidazole-7-carboximidamide 3264
    357 N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(((4-methylmorpholin-2-yl)methyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide 3239
    358 N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(((1-methyl-1H-pyrazol-5-yl)methyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide 8791
    368 N-(3-chloro-4-fluorophenyl)-4-fluoro-N'-hydroxy-2-((2-morpholinoethyl)amino)-1H-benzo[d]imidazole-7-carboximidamide 4004
    369 N-(3-chloro-4-fluorophenyl)-N'-hydroxy-N-methyl-1H-imidazo[4,5-b]pyridine-7-carboximidamide >10000
    370 2-amino-N-(3-chloro-4-fluorophenyl)-5-fluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide 1078
    371 2-amino-N-(3-chlorophenyl)-5-fluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide 644
    372 2-amino-N-(3-bromophenyl)-5-fluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide 483
    373 2-amino-N-(3-bromo-4-fluorophenyl)-5-fluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide 736
    374 N-(3-chloro-4-fluorophenyl)-2-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide 2399
    375 N-(3-chloro-4-fluorophenyl)-2-((2-(diethylamino)ethyl)amino)-4-fluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide 1190
    376 N-(3-chloro-4-fluorophenyl)-4-fluoro-N'-hydroxy-2-((2-(pyrrolidin-1-yl)ethyl)amino)-1H-benzo[d]imidazole-7-carboximidamide 1258
    377 N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((2-morpholinopropyl)amino)-1H-benzo[d]imidazole-7-carboximidamide 838
    378 N-(3-chloro-4-fluorophenyl)-2-((1-(dimethylamino)propan-2-yl)amino)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide 1396
    379 N-(3-chloro-4-fluorophenyl)-2-((2-(dimethylamino)ethyl)amino)-5-fluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide 435
    380 N-(3-chloro-4-fluorophenyl)-5-fluoro-N'-hydroxy-2-((2-(pyrrolidin-1-yl)ethyl)amino)-1H-benzo[d]imidazole-7-carboximidamide 1388
    381 N-(3-chloro-4-fluorophenyl)-2-((3-(dimethylamino)-2,2-dimethylpropyl)amino)-4-fluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide 3025
    382 N-(3-bromo-4-fluorophenyl)-2-((2-(dimethylamino)ethyl)amino)-4-fluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide 608
    383 N-(3-bromophenyl)-2-((2-(dimethylamino)ethyl)amino)-4-fluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide 319
    384 N-(3-chlorophenyl)-2-((2-(dimethylamino)ethyl)amino)-4-fluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide 290
    385 N-(3-chlorophenyl)-2-((3-(dimethylamino)propyl)amino)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide 580
    386 N-(3-bromophenyl)-2-((3-(dimethylamino)propyl)amino)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide 559
    387 N-(3-bromo-4-fluorophenyl)-2-((3-(dimethylamino)propyl)amino)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide 692
    388 N-(3-chloro-4-fluorophenyl)-2-((3-(dimethylamino)propyl)amino)-4-fluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide 939
    389 N-(3-chloro-4-fluorophenyl)-2-((3-(dimethylamino)propyl)amino)-5-fluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide 1157
    390 2-((2-(benzyl(methyl)amino)ethyl)amino)-N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide 1017
    391 N-(3-chloro-4-fluorophenyl)-2-(2-((cyclohexylmethyl)(methyl)amino)ethyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide 1480
    392 N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(2-(methyl(neopentyl)amino)ethyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide 1226
    393 N-(3-chloro-4-fluorophenyl)-2-(2-(cyclohexyl(methyl)amino)ethyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide 1794
    394 N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((2-(methyl((tetrahydro-2H-pyran-4-yl)methyl)amino)ethyl)amino)-1H-benzo[d]imidazole-7-carboximidamide 332
    395 N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((2-(methylamino)ethyl)amino)-1H-benzo[d]imidazole-7-carboximidamide 757
    396 2-(2-(benzyl(methyl)amino)ethyl)-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide 790
    397 N-(3-chloro-4-fluorophenyl)-2-((2-((2-ethylbutyl)(methyl)amino)ethyl)amino)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide 1317
    398 N-(3-chloro-4-fluorophenyl)-2-((2-((cyclopropylmethyl)(methyl)amino)ethyl)amino) -4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide 555
    399 N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(2-(methyl((tetrahydro-2H-pyran-4-yl)methyl)amino)ethyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide 1329
    400 2-(2-(((1,4-dioxan-2-yl)methyl)(methyl)amino)ethyl)-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide 2814
    401 N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(2-(methyl(2-(tetrahydro-2H-pyran-4-yl)ethyl)amino)ethyl)-1H-imidazo[4,5-b] pyridine-7-carboximidamide 581
    402 N-(3-chloro-4-fluorophenyl)-2-((2-(cyclopropylamino)ethyl)amino)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide 561
    403 N-(3-chloro-4-fluorophenyl)-2-((2-(cyclopropyl(ethyl)amino)ethyl)amino)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide 192
    404 N-(2-((7-(N-(3-chloro-4-fluorophenyl)-N'-hydroxycarbamimidoyl)-1H-imidazo[4,5-b]pyridin-2-yl)amino)ethyl)acetamide >10000
    405 N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((2-(methylsulfonamido)ethyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide 7112
    406 N-(3-chloro-4-fluorophenyl)-2-((2-(cyclopropyl(isopropyl)amino)ethyl)amino)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide 185
    407 N-(3-chloro-4-fluorophenyl)-2-((2-(cyclopropyl(2-hydroxyethyl)amino)ethyl)amino)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide 2122
    427 N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(((5-methyl-1,3,4-oxadiazol-2-yl)methyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide 1071
    429 N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-(((4-methylmorpholin-3-yl)methyl)amino)-1H-benzo[d]imidazole-7-carboximidamide 1346
    430 N-(3-bromophenyl)-2-((2-(dimethylamino)ethyl)amino)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide 180
    431 N-(3-chlorophenyl)-2-((2-(dimethylamino)ethyl)amino)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide 139
    432 N-(3-bromo-4-fluorophenyl)-2-((2-(dimethylamino)ethyl)amino)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide 253
    433 N-(3-chloro-4-fluorophenyl)-4,5-difluoro-2-((3-morpholinopropyl)amino)-1H-benzo[d]imidazole-7-carboxamide 882
    434 N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((3-(pyrrolidin-1-yl)propyl)amino)-1H-benzo[d]imidazole-7-carboximidamide 1240
    435 2-(((3R)-4-amino-1-methylpyrrolidin-3-yl)amino)-N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide 1814
    436 N-(3-chloro-4-fluorophenyl)-2-((2-(dimethylamino)-2-phenylethyl)amino)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide 2015
    437 N-(3-chloro-4-fluorophenyl)-2-(((1R,2R)-2-(dimethylamino)cyclohexyl)amino)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide 998
    438 N-(3-chloro-4-fluorophenyl)-2-(((1-(dimethylamino)cyclopentyl)methyl)amino)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide 838
    439 N-(3-chloro-4-fluorophenyl)-2-(((1S*,3S*)-3-(dimethylamino)cyclohexyl)amino)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide 6799
    440 N-(3-chloro-4-fluorophenyl)-2-(((1S,3R)-3-(dimethylamino)cyclohexyl)amino)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide 6660
    441 N-(3-chloro-4-fluorophenyl)-2-(((1-(dimethylamino)cyclobutyl)methyl)amino)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide >10000
    442 N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((1-methylpiperidin-4-yl)amino)-1H-benzo[d]imidazole-7-carboximidamide 2881
    443 N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((1-methylpiperidin-3-yl)amino)-1H-benzo[d]imidazole-7-carboximidamide 389
    444 N-(3-chloro-4-fluorophenyl)-2-(((1S,2S)-2-(dimethylamino)cyclohexyl)amino)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide 3144
    445 (S)-N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-(piperidin-3-ylamino)-1H-benzo[d]imidazole-7-carboximidamide 1946
    446 (R)-N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-(piperidin-3-ylamino)-1H-benzo[d]imidazole-7-carboximidamide 1490
    447 (S)-N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((1-methylpyrrolidin-3-yl)amino)-1H-benzo[d]imidazole-7-carboximidamide 325
    448 N-(3-chloro-4-fluorophenyl)-2-((3-(dimethylamino)-2-hydroxypropyl)amino)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide 1118
    449 N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((2-(4-methyl-3-oxopiperazin-1-yl)ethyl)amino)-1H-benzo[d]imidazole-7-carboximidamide 6249
    450 N-(3-chloro-4-fluorophenyl)-2-(((1-(dimethylamino)cyclohexyl)methyl)amino)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide 1586
    451 N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((1-methylazepan-3-yl)amino)-1H-benzo[d]imidazole-7-carboximidamide 205
    452 (S)-N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((2-(3-hydroxypyrrolidin-1-yl)ethyl)amino)-1H-benzo[d]imidazole-7-carboximidamide 568
    453 N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((1-(2-methoxyethyl)piperidin-3-yl)amino)-1H-benzo[d]imidazole-7-carboximidamide 651
    454 N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((1-(2-methoxyethyl)pyrrolidin-3-yl)amino)-1H-benzo[d]imidazole-7-carboximidamide 247
    455 N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((1-isopropylpiperidin-3-yl)amino)-1H-benzo[d]imidazole-7-carboximidamide 376
    456 N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((2-(3-methoxyazetidin-1-yl)ethyl)amino)-1H-benzo[d]imidazole-7-carboximidamide 274
    457 (R)-N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((1-methylpyrrolidin-3-yl)amino)-1H-benzo[d]imidazole-7-carboximidamide 271
    458 N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-(((3R,4R)-4-methoxy-1-methylpyrrolidin-3-yl)amino)-1H-benzo[d]imidazole-7-carboximidamide 261
    459 (S)-N-(3-chlorophenyl)-4,5-difluoro-N'-hydroxy-2-((1-methylpiperidin-3-yl)amino)-1H-benzo[d]imidazole-7-carboximidamide 337
    460 (R)-N-(3-chlorophenyl)-4,5-difluoro-N'-hydroxy-2-((1-methylpiperidin-3-yl)amino)-1H-benzo[d]imidazole-7-carboximidamide 193
    461 N-(3-chloro-4-fluorophenyl)-2-((2-(dimethylamino)cyclopentyl)amino)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide 472
    462 (S)-2-(azepan-3-ylamino)-N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide 1429
    463 (R)-2-(azepan-3-ylamino)-N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide 1020
    464 N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-(pyrrolidin-3-ylamino)-1H-benzo[d]imidazole-7-carboximidamide 2346
    465 (R)-N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((1-(oxetan-3-yl)piperidin-3-yl)amino)-1H-benzo[d]imidazole-7-carboximidamide 957
    466 N-(3-chloro-4-fluorophenyl)-2-(((1,4-dimethylpiperidin-2-yl)methyl)amino)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide 685
    467 N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((morpholin-3-ylmethyl)amino)-1H-benzo[d]imidazole-7-carboximidamide 2116
    468 N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-(((3R,4S)-4-hydroxypyrrolidin-3-yl)amino)-1H-benzo[d]imidazole-7-carboximidamide >10000
    469 N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-(((1R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl)amino)-1H-benzo[d]imidazole-7-carboximidamide 959
    470 (S)-N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((2-(2-(trifluoromethyl)pyrrolidin-1-yl)ethyl)amino)-1H-benzo[d]imidazole-7-carboximidamide 4200
    471 N-(3-chloro-4-fluorophenyl)-4,5-difluoro-2-(((hexahydro-1H-pyrrolizin-7a-yl)methyl)amino)-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide 852
    472 N-(3-chloro-4-fluorophenyl)-2-(((3,3-dimethylazetidin-2-yl)methyl)amino)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide 2452
    473 N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((4-(pyrrolidin-1-yl)tetrahydro-2H-pyran-3-yl)amino)-1H-benzo[d]imidazole-7-carboximidamide 1034
    474 2-(((1S,2R)-2-aminocyclohexyl)amino)-N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide 7584
    475 N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)amino)-1H-benzo[d]imidazole-7-carboximidamide 1993
    476 N-(3-chloro-4-fluorophenyl)-2-(((3S,4S)-4-(diethylamino)tetrahydrofuran-3-yl)amino)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide 468
    477 2-((1,4-oxazepan-6-yl)amino)-N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide 1525
    478 N-(3-chloro-4-fluorophenyl)-2-((2-((2S,6R)-2,6-dimethylmorpholino)ethyl)amino)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide 1011
    479 N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(((3R,4R)-4-methoxy-1-methylpyrrolidin-3-yl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide 1069
    480 N-(3-chloro-4-fluorophenyl)-2-(((3R,4R)-4-(diethylamino)tetrahydrofuran-3-yl)amino)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide 1194
    481 (S)-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((2-(2-(trifluoromethyl)pyrrolidin-1-yl)ethyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide 760
    482 (R)-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(((4-methylmorpholin-3-yl)methyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide 2653
    483 N-(3-chloro-4-fluorophenyl)-2-((2-(2,6-dimethylmorpholino)propyl)amino)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide 668
    484 N-(3-chloro-4-fluorophenyl)-2-((2-(2,6-dimethylmorpholino)-2-methylpropyl)amino)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide 566
    485 N-(3-chloro-4-fluorophenyl)-2-((2-(2,5-dimethylmorpholino)ethyl)amino)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide 639
    486 N-(3-chloro-4-fluorophenyl)-2-(((1R,2R)-2-(dimethylamino)cyclopentyl)amino)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide 284
    487 N-(3-chloro-4-fluorophenyl)-2-((2-(dimethylamino)ethyl)thio)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide 1361
    488 N-(3-chloro-4-fluorophenyl)-2-((2-(dimethylamino)ethyl)thio)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide 3012
    489 N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((2-(2-(hydroxymethyl)piperidin-1-yl)ethyl)amino)-1H-benzo[d]imidazole-7-carboximidamide 289
    490 N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((2-(2-(hydroxymethyl)pyrrolidin-1-yl)ethyl)amino)-1H-benzo[d]imidazole-7-carboximidamide 186
    491 N-(3-chloro-4-fluorophenyl)-2-((2-(3,3-difluoropyrrolidin-1-yl)ethyl)amino)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide 917
    492 N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((2-sulfamoylethyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide 5660
    493 N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((2-(methylsulfonyl)ethyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide 7215
    494 N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((pyrimidin-2-ylmethyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide >10000

Claims (16)

  1. A compound of Formula I:
    Figure imgb0919
     wherein
    R1 is mono- or bicyclic aryl or heteroaryl, wherein each mono- or bicyclic aryl or heteroaryl is optionally substituted with one, two, or three substituents independently selected from hydroxyl, halo, -CN, C1-6 haloalkyl, C1-6 haloalkoxy, C1-6 alkoxy, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C3-6 cycloalkyl, wherein two of the optional substituents can join to form an additional partially saturated heterocyclic ring; and
    wherein each C1-6 alkoxy, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C3-6 cycloalkyl is optionally substituted with one, two, or three substituents independently selected from hydroxyl, halo, -CN, -N(R20)(R22) and C3-6 cycloalkyl;
    X is N or CR2c;
    R2a, R2b, and R2c are independently hydrogen, hydroxyl, halo, CN, C1-6 haloalkyl, C1-6 haloalkoxy, C1-6 alkoxy, or C1-6 alkyl;
    R2d and R2e are independently hydrogen, C1-6 haloalkyl, C1-6 haloalkoxy, or C1-6 alkyl;
    n and m are independently 0, 1, 2, or 3;
    each Rn and Rm is independently hydrogen, hydroxyl, halo, C1-6 alkoxy, C1-6 alkyl, C3-6 cycloalkyl, aryl, heterocyclyl, or heteroaryl; or two Rn or Rm join to form a C3-6 cycloalkyl; and
    wherein each C1-6 alkoxy, C1-6 alkyl, C3-6 cycloalkyl, aryl, heterocyclyl, or heteroaryl is optionally substituted with one, two, or three substituents independently selected from hydroxyl, halo, -CN, -N(R20)(R22), C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 haloalkoxy, C1-6 alkoxy, C1-6 alkyl, and C3-6 cycloalkyl;
    L is a bond, -NR3-, -C(O)-NR3-, -NR3-C(O)-, -NR3SO2-, -NR3SO2-NR3-, -SO2NR3-, -O-, -S-, or -S(O)t-, where t is 0, 1 or 2;
    each R3 is independently hydrogen, C1-6 alkyl, C3-6 cycloalkyl, aryl, heterocyclyl, or heteroaryl; and
    R1 is hydrogen, C1-6 alkyl, C1-6 alkoxy, -C(O)R20, -C(O)OR20, -NC(O)OR20, -N(R20)(R22), -C(O)N(R20)(R22), -SO2R20, -N(R20)SO2(R21), -N(R20)SO2-N(R21)(R22), -SO2N(R21)(R22), C3-15 cycloalkyl, aryl, heteroaryl, or heterocyclyl, provided that when Rt is C1-6 alkoxy, -NC(O)OR20, -N(R20)(R22), -N(R20)SO2(R21), -N(R20)SO2-N(R21)(R22), or -SO2N(R20)(R22), and m is 0, then L is a bond;
    wherein said C1-6 alkyl, C1-6 alkoxy, C3-15 cycloalkyl, aryl, heterocyclyl, or heteroaryl is optionally substituted with one, two, or three substituents independently selected from hydroxyl, halo, -NO2, C1-6 haloalkyl, C1-6 haloalkoxy, -C(O)R20, -N(R20)(R22), -SO2R20, -N(R20)SO2(R21), -N(R20)SO2-N(R21)(R22), -SO2N(R20)(R22), C3-6 cycloalkyl, -CN, C1-6 alkoxy, C1-6 alkyl, and heterocyclyl; and wherein said heterocyclyl is optionally substituted with one or two oxo;
    wherein said C3-6 cycloalkyl, C1-6 alkyl or C1-6 alkoxy is optionally substituted with one, two, or three substituents independently selected from hydroxyl, halo, -NO2, C1-6 haloalkyl, C1-6 haloalkoxy, C1-6 alkoxy, -N(R20)(R22), -SO2R20, -N(R20)SO2(R22), -N(R20)SO2-N(R21)(R22)-, and -SO2N(R20)(R22); and said C1-6 alkyl is optionally substituted with aryl;
    R20, R21, and R22 are independently selected from hydrogen, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, aryl, heterocyclyl, and heteroaryl;
    wherein said aryl, heterocyclyl, or heteroaryl is optionally substituted with one, two, or three halogen;
    or a pharmaceutically acceptable salt or mixture thereof.
  2. The compound of claim 1, wherein the compound is represented by Formula IV:
    Figure imgb0920
     or a pharmaceutically acceptable salt or mixture thereof.
  3. The compound of claim 1 or 2 wherein
    (i) R1 is bicyclic aryl or heteroaryl optionally substituted with one, two, or three substituents independently selected from hydroxyl, halo, -CN, C1-6 haloalkyl, C1-6 haloalkoxy, C1-6 alkoxy, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C3-6 cycloalkyl; or a pharmaceutically acceptable salt or mixture thereof;
    (ii) R1 is phenyl optionally substituted with one, two, or three substituents independently selected from hydroxyl, halo, -CN, C1-6 haloalkyl, C1-6 haloalkoxy, C1-6 alkoxy, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C3-6 cycloalkyl, and wherein two of the optional substituents can join to form an additional partially saturated heterocyclic ring; or a pharmaceutically acceptable salt or mixture thereof; or
    (iii) R1 is selected from the group consiting of
    Figure imgb0921
    Figure imgb0922
    Figure imgb0923
    Figure imgb0924
    Figure imgb0925
    Figure imgb0926
    Figure imgb0927
    Figure imgb0928
    Figure imgb0929
    Figure imgb0930
    Figure imgb0931
     or a pharmaceutically acceptable salt or mixture thereof.
  4. The compound of any one of the preceding claims wherein X is N; or a pharmaceutically acceptable salt or mixture thereof.
  5. The compound of any one of claims 1-3 wherein X is CR2c; or a pharmaceutically acceptable salt or mixture thereof.
  6. The compound of any one of the preceding claims wherein L is a bond; or a pharmaceutically acceptable salt or mixture thereof.
  7. The compound of any one of claims 1-4 wherein L is -NR3; or a pharmaceutically acceptable salt or mixture thereof.
  8. The compound of any one of the preceding claims wherein Rt is hydrogen; or a pharmaceutically acceptable salt or mixture thereof.
  9. The compound of any one of claims 1-6 wherein
    (a) Rt is C1-6 alkyl optionally substituted with one, two, or three substituents independently selected from hydroxyl, halo, -NO2, C1-6 haloalkyl, C1-6 haloalkoxy, C3-6 cycloalkyl, -CN, and C1-6 alkoxy; or a pharmaceutically acceptable salt or mixture thereof; or
    (b) Rt is C3-15 cycloalkyl, aryl, heteroaryl, or heterocyclyl, wherein said cycloalkyl, aryl, heterocyclyl, or heteroaryl is optionally substituted with one, two, or three substituents independently selected from hydroxyl, halo, -NO2, C1-6 haloalkyl, C1-6 haloalkoxy, C3-6 cycloalkyl, -CN, C1-6 alkoxy and C1-6 alkyl; or a pharmaceutically acceptable salt or mixture thereof.
  10. The compound of any one of claims 1-5 wherein L is -NR3 and Rt is C3-15 cycloalkyl, aryl, heteroaryl, or heterocyclyl, wherein said cycloalkyl, aryl, heterocyclyl, or heteroaryl is optionally substituted with one, two, or three substituents independently selected from hydroxyl, halo, -NO2, C1-6 haloalkyl, C1-6 haloalkoxy, C3-6 cycloalkyl, -CN, and C1-6 alkoxy; or a pharmaceutically acceptable salt or mixture thereof.
  11. The compound of any one of claims 1-4 wherein the group
    Figure imgb0932
     is selected from the group consisting of:
    -H,
    Figure imgb0933
    Figure imgb0934
    Figure imgb0935
    Figure imgb0936
    Figure imgb0937
    Figure imgb0938
    Figure imgb0939
    Figure imgb0940
    Figure imgb0941
    Figure imgb0942
    Figure imgb0943
    Figure imgb0944
    Figure imgb0945
    Figure imgb0946
    Figure imgb0947
    Figure imgb0948
    Figure imgb0949
    Figure imgb0950
    Figure imgb0951
    Figure imgb0952
    Figure imgb0953
    Figure imgb0954
    Figure imgb0955
    Figure imgb0956
    Figure imgb0957
    Figure imgb0958
    Figure imgb0959
    Figure imgb0960
    Figure imgb0961
    Figure imgb0962
    Figure imgb0963
    Figure imgb0964
    Figure imgb0965
    Figure imgb0966
    Figure imgb0967
    Figure imgb0968
    Figure imgb0969
    Figure imgb0970
    Figure imgb0971
    Figure imgb0972
    Figure imgb0973
    Figure imgb0974
    Figure imgb0975
    Figure imgb0976
    Figure imgb0977
    Figure imgb0978
    Figure imgb0979
    Figure imgb0980
    Figure imgb0981
    Figure imgb0982
    Figure imgb0983
    Figure imgb0984
    Figure imgb0985
    Figure imgb0986
    Figure imgb0987
    Figure imgb0988
    Figure imgb0989
    Figure imgb0990
    Figure imgb0991
    Figure imgb0992
    Figure imgb0993
    Figure imgb0994
    Figure imgb0995
    Figure imgb0996
    Figure imgb0997
    Figure imgb0998
    Figure imgb0999
     or a pharmaceutically acceptable salt or mixture thereof.
  12. The compound of claim 1 selected from the group consisting of:
    N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-4-methyl-1H-benzo[d]imidazole-7-carboximidamide,
    N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-4-(trifluoromethoxy)-1H-benzo[d]imidazole-7-carboximidamide,
    N-(3-Chloro-4-fluorophenyl)-6-fluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide,
    N-(3-Chloro-4-fluorophenyl)-5-fluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide,
    N-(3-Chloro-4-fluorophenyl)-4-fluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide,
    4-Chloro-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide,
    N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-4-(trifluoromethyl)-1H-benzo[d]imidazole-7-carboximidamide,
    N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide,
    N-(3-Chloro-4-fluorophenyl)-6-fluoro-N'-hydroxy-7-methyl-3H-benzimidazole-4-carboximidamide,
    N-(3-Chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide,
    6-Chloro-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-1H-benzo[d]imidazole-4-carboximidamide,
    4-Bromo-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide,
    2-Amino-N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide,
    2-Amino-N-(3-bromo-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide,
    2-Amino-N-(3-bromophenyl)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide,
    2-Amino-N-(3-chlorophenyl)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide,
    2-Amino-4,5-difluoro-N-(4-fluoro-3-(trifluoromethyl)phenyl)-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide,
    2-Amino-N-(3-bromophenyl)-4-fluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide,
    2-Amino-N-(3-bromo-4-fluorophenyl)-4-fluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide,
    2-Amino-N-(3-chlorophenyl)-4-fluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide,
    2-Amino-4-fluoro-N-(4-fluoro-3-(trifluoromethyl)phenyl)-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide,
    2-Amino-N-(3-chloro-4-fluorophenyl)-4-fluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide,
    N-(3-Chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((2-morpholmoethyl)amino)-1H-benzo[d]imidazole-7-carboximidamide,
    N-(3-Chlorophenyl)-4,5-difluoro-N'-hydroxy-2-(((3-methoxypropyl)amino)methyl)-1H-benzo[d]imidazole-7-carboximidamide,
    N-(3-Chlorophenyl)-2-(((cyclopropylmethyl)amino)methyl)-4,5-difluoro-N-hydroxy-1H-benzo[d]imidazole-7-carboximidamide,
    N-(3-Chlorophenyl)-2-((dimethylamino)methyl)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide,
    N-(3-Chlorophenyl)-4,5-difluoro-N'-hydroxy-2-((isopropylamino)methyl)-1H-benzo[d]imidazole-7-carboximidamide,
    N-(3-Chlorophenyl)-2-((ethylamino)methyl)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide,
    N-(3-Chlorophenyl)-4,5-difluoro-N'-hydroxy-2-(hydroxymethyl)-1H-benzo[d]imidazole-7-carboximidamide,
    N-(3-Chlorophenyl)-4,5-difluoro-N'-hydroxy-2-((methylamino)methyl)-1H-benzo[d]imidazole-7-carboximidamide,
    2-(Aminomethyl)-N-(3-chlorophenyl)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide,
    N-(3-Chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-morpholino-1H-benzo-[d]imidazole-7-carboximidamide,
    N-(3-Chloro-4-fluorophenyl)-4-fluoro-N'-hydroxy-2-((2-(methylsulfonyl)ethyl)amino)-1H-benzo[d]imidazole-7-carboximidamide,
    N-(3-Chloro-4-fluorophenyl)-4-fluoro-N'-hydroxy-2-((2-morpholinoethyl)amino)-1H-benzo[d]imidazole-7-carboximidamide,
    N-(3-Chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((2-(methylsulfonyl)ethyl)amino)-1H-benzo[d]imidazole-7-carboximidamide,
    N-(3-Chloro-4-fluorophenyl)-2-((2-(4,4-difluoropiperidin-1-yl)ethyl)amino)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide,
    N-(3-Chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((1-morpholinopropan-2-yl)amino)-1H-benzo[d]imidazole-7-carboximidamide,
    N-(3-Chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-(methylamino)-1H-benzo[d]imidazole-7-carboximidamide,
    N-(3-Chloro-4-fluorophenyl)-2-((3-(dimethylamino)propyl)amino)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide,
    N-(3-Chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((2-methoxyethyl)amino)-1H-benzo[d]imidazole-7-carboximidamide,
    N-(3-Chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((2-(pyrrolidin-1-yl)ethyl)amino)-1H-benzo[d]imidazole-7-carboximidamide,
    N-(3-Chloro-4-fluorophenyl)-2-((2-(diethylamino)ethyl)amino)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide,
    N-(3-Chloro-4-fluorophenyl)-2-((2-(dimethylamino)ethyl)amino)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide,
    N-(3-Chlorophenyl)-4,5-difluoro-N'-hydroxy-2-(1-methylpiperidin-3-yl)-1H-benzo[d]imidazole-7-carboximidamide,
    N-(3-Chloro-4-fluorophenyl)-6,7-difluoro-N'-hydroxy-2-(((3-methoxypropyl)amino)methyl)-1H-benzo[d]imidazole-4-carboximidamide,
    N-(3-Chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-(hydroxymethyl)-1H-benzo[d]imidazole-7-carboximidamide,
    2-(Aminomethyl)-N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide,
    N-(3-Chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((methylamino)methyl)-1H-benzo[d]imidazole-7-carboximidamide,
    N-(3-Chloro-4-fluorophenyl)-2-(((cyclopropylmethyl)amino)methyl)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide,
    N-(3-Chloro-4-fluorophenyl)-2-((ethylamino)methyl)-6,7-difluoro-N'-hydroxy-1H-benzo[d]imidazole-4-carboximidamide,
    N-(3-Chloro-4-fluorophenyl)-6,7-difluoro-N'-hydroxy-2-((isopropylamino)methyl)-1H-benzo[d]imidazole-4-carboximidamide,
    N-(3-Chloro-4-fluorophenyl)-2-((dimethylamino)methyl)-6,7-difluoro-N'-hydroxy-1H-benzo[d]imidazole-4-carboximidamide,
    N-(3-Chloro-4-fluorophenyl)-2-(2-(dimethylamino)ethyl)-6,7-difluoro-N'-hydroxy-1H-benzo[d]imidazole-4-carboximidamide,
    N-(3-Bromo-4-fluorophenyl)-2-(2-(dimethylamino)ethyl)-6,7-difluoro-N'-hydroxy-1H-benzo[d]imidazole-4-carboximidamide,
    N-(3-Bromophenyl)-2-(2-(dimethylamino)ethyl)-6,7-difluoro-N'-hydroxy-1H-benzo[d]imidazole-4-carboximidamide,
    N-(3-Chlorophenyl)-2-(2-(dimethylamino)ethyl)-6,7-difluoro-N'-hydroxy-1H-benzo[d]imidazole-4-carboximidamide,
    N-(3-Chloro-4-fluorophenyl)-6,7-difluoro-N'-hydroxy-2-(2-(methylamino)ethyl)-1H-benzo[d]imidazole-4-carboximidamide,
    N-(3-Chloro-4-fluorophenyl)-2-(2-(diethylamino)ethyl)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide,
    N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(5-Chloro-2-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(5-Bromo-2,4-difluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(5-Chloro-2,4-difluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3,5-Dichloro-4-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-Chloro-2,4-difluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-Cyclopropyl-4-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N'-Hydroxy-N-(4-(trifluoromethoxy)phenyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(Benzofuran-4-yl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(Benzofuran-6-yl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(Benzofuran-7-yl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(benzofuran-5-yl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(5-Bromo-2-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-Bromo-5-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N'-Hydroxy-N-(3-(trifluoromethyl)phenyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-Fluoro-5-(trifluoromethyl)phenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(2,5-Dichlorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(6-Fluoro-[1,1'-biphenyl]-3-yl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-(But-1-yn-1-yl)-4-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-(Cyclopropylethynyl)-4-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-Bromophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-Bromo-4-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-Chlorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(4-Fluoro-3-(trifluoromethyl)phenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(4-Fluoro-3-(prop-1-yn-1-yl)phenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-Bromo-4-chlorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3,4-Dichlorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(4-Chlorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(4-Bromophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(4-Fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-Cyano-4-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N'-Hydroxy-N-(4-(trifluoromethyl)phenyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N'-Hydroxy-N-(3-methoxyphenyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(4-Fluoro-3-isopropylphenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N'-Hydroxy-N-(p-tolyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N'-(3-Ethynylphenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-Ethylphenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-Ethynyl-4-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-(Difluoromethyl)phenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-Hydroxy-N-(3-(trifluorometlioxy)phenyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-Hydroxy-N-phenyl-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(4-Fluoro-3-(trifluoromethoxy)phenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-Hydroxy-N-(naphthalen-2-yl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-Chloronaphthalen-2-yl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N'-hydroxy-N-(naphthalen-1-yl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(4-Chloronaphthalen-1-yl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(4-Fluoro-3-methoxyphenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-methyl-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-Chloro-4-fluorophenyl)-2-ethyl-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-Chloro-4-fluorophenyl)-2-cyclopropyl-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-(methoxymethyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    4-(3-Chloro-4-fluorophenyl)-3-(2-(hydroxymethyl)-1H-imidazo[4,5-b]pyridin-7-yl)-1,2,4-oxadiazol-5(4H)-one,
    N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-(morpholinomethyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-Chloro-4-fluorophenyl)-2-((dimethylamino)methyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-Chloro-4-fluorophenyl)-2-((ethylamino)methyl)-N'-hydroxy-1H-imidazo [4,5-b]pyridine-7-carboximidamide,
    2-((Benzylamino)methyl)-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-((isopropylamino)methyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-Chloro-4-fluorophenyl)-2-(((cyclopropylmethyl)amino)methyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-(((2,2,2-trifluoroethyl)amino)methyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-Chloro-4-fluorophenyl)-2-((cyclopropylamino)methyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-(((3-methoxypropyl)amino)methyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-(((pyridin-2-ylmethyl)amino)methyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-(((3-methoxypropyl)(methyl)amino)methyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-(((2-methoxybenzyl)amino)methyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-(((2-methoxyethyl)amino)methyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-(((2-(pyridin-2-yl)ethyl)amino)methyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-(((pyridin-3-ylmethyl)amino)methyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-((((tetrahydro-2H-pyran-2-yl)methyl)amino)methyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-((phenylamino)methyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-((((tetrahydro-2H-pyran-3-yl)methyl)amino)methyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-(((pyrimidin-2-ylmethyl)amino)methyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-(((3-morpholinopropyl)amino)methyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-(((tetrahydro-2H-pyran-4-yl)amino)methyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-(((pyridin-4-ylmethyl)amino)methyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-(((pyrazin-2-ylmethyl)amino)methyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-((((tetrahydrofuran-3-yl)methyl)amino)methyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-Chloro-4-fluorophenyl)-2-(((2-(dimethylamino)ethyl)amino)methyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-(((2-(pyrimidin-2-yl)ethyl)amino)methyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-(((3-hydroxypropyl)amino)methyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-(pyrrolidin-1-ylmethyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-(piperidin-1-ylmethyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-((neopentylamino)methyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-Chloro-4-fluorophenyl)-2-(((2,2-difluoroethyl)amino)methyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-(((3-hydroxy-2,2-dimethylpropyl)amino)methyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-(((thiazol-2-ylmethyl)amino)methyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-((7-(N-(3-Chloro-4-fluorophenyl)-N'-hydroxycarbamimidoyl)-1H-imidazo[4,5-b]pyridin-2-yl)methyl)acetamide,
    N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-(thiophen-2-yl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-(pyridin-3-yl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-(1H-pyrrol-2-yl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-(1H-imidazol-2-yl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-(1H-pyrazol-5-yl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-(4-methyl-1H-imidazol-2-yl)-1H-imidazo [4,5-b]pyridine-7-carboximidamide,
    N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-(pyrrolidin-2-yl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    2-Amino-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-Chloro-4-fluorophenyl)-2-(cyclopropylamino)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-(phenylamino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-(phenethylamino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-((2,2,2-trifluoroethyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-(methylamino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    Isopropyl (7-(N-(3-chloro-4-fluorophenyl)-N'-hydroxycarbamimidoyl)-1H-imidazo[4,5-b]pyridin-2-yl)carbamate,
    Ethyl (7-(N-(3-chloro-4-fluorophenyl)-N'-hydroxycarbamimidoyl)-1H-imidazo[4,5-b]pyridin-2-yl)carbamate,
    N-(3-Chloro-4-fluorophenyl)-2-((cyclopropylmethyl)amino)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-Chloro-4-fluorophenyl)-2-((3,3-difluorocyclobutyl)amino)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-Chloro-4-fluorophenyl)-2-(ethylamino)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-Chloro-4-fluorophenyl)-2-(cyclobutylamino)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-(isopropylamino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-Chlorophenyl)-N'-hydroxy-2-(methylamino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-Chloro-4-fluorophenyl)-2-((2-(diethylamino)ethyl)amino)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-((2-morpholinoethyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-Chloro-4-fluorophenyl)-2-(dimethylamino)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    2-(Chloromethyl)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-N'-hydroxy-3H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(4-Fluoro-3-(trifluoromethyl)phenyl)-N'-hydroxy-2-(hydroxymethyl)-3H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-(1-hydroxyethyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-(hydroxy(phenyl)methyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-Chloro-4-fluorophenyl)-2-(cyclopropyl(hydroxy)methyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-(2-hydroxypropan-2-yl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-(2,2,2-trifluoro-1-hydroxyethyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-(hydroxymethyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-((methylamino)methyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    2-(Aminomethyl)-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-(phenylsulfonamidomethyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-(methylsulfonamidomethyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-((pyrimidin-2-ylamino)methyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-(2-hydroxyethyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-Chloro-4-fluorophenyl)-2-(2-(dimethylamino)ethyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-Chloro-4-fluorophenyl)-2-(2-(diethylamino)ethyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-Chloro-4-fluorophenyl)-2-(2-((cyclopropylmethyl)(methyl)amino)ethyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-Chloro-4-fluorophenyl)-2-(2-((2,2-difluoroethyl)(methyl)amino)ethyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-(2-(methylamino)ethyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    2-(2-Aminoethyl)-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-(2-((2-methoxyethyl)amino)ethyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-(2-morpholinoethyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-(2-(piperidin-1-yl)ethyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-(2-(pyrrolidin-1-yl)ethyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-(2-((2-methoxyethyl)(methyl)amino)ethyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-Chloro-4-fluorophenyl)-2-(2-(dimethylamino)-1-hydroxyethyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-((isobutylamino)methyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-3-methyl-3H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-[2-(2-methoxyethylamino)ethyl]-3H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-Chloro-4-fluorophenyl)-2-[3-(dimethylamino)propyl]-6,7-difluoro-N'-hydroxy-3H-benzimidazole-4-carboximidamide,
    N-(3-Chloro-4-fluorophenyl)-7-fluoro-N'-hydroxy-2-(3-morpholin-4-ylpropylamino)-3H-benzimidazole-4-carboximidamide,
    N-(3-Chloro-4-fluorophenyl)-2-[2-(dimethylamino)ethylamino]-7-fluoro-N'-hydroxy-3H-benzimidazole-4-carboximidamide,
    N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-[(1-methylpiperidin-2-yl)methylamino]-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-[(1-methylpyrrolidin-3-yl)amino]-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-2-(2-(ethylamino)ethyl)-N'-hydroxy-3H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(2-(isopropylamino)ethyl)-3H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(2-(isobutylamino)ethyl)-3H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-2-(2-(cyclopropylamino)ethyl)-N'-hydroxy-3H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-2-(2-((cyclopropylmethyl)amino)ethyl)-N'-hydroxy-3H-imidazo[4,5-b]pyridine-7-carboximidamide,
    2-(2-(2-amino-4,5-dihydro-1H-imidazol-1-yl)ethyl)-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-(2-(methylsulfonamido)ethyl)-1H-benzo[d]imidazole-7-carboximidamide,
    2-(2-aminoethyl)-N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((2-methoxyethyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    tert-butyl (2-(7-(N-(3-chloro-4-fluorophenyl)-N'-hydroxycarbamimidoyl)-4,5-difluoro-1H-benzo[d]imidazol-2-yl)ethyl)carbamate,
    N-(3-chloro-4-fluorophenyl)-2-((2-(4,4-difluoropiperidin-1-yl)ethyl)amino)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-2-((2-(dimethylamino)ethyl)amino)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((2-(methylamino)ethyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((1-methylazepan-3-yl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-2-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((2-((2-methoxyethyl)(methyl)amino)ethyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-2-((2-((2,2-difluoroethyl)(methyl)amino)ethyl)amino)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((3-morpholinopropyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((2-(piperidin-1-yl)ethyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-2-((2-cyclohexylethyl)amino)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((2-(tetrahydro-2H-pyran-4-yl)ethyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-2-((2,2-difluoroethyl)amino)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(oxetan-3-ylamino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((tetrahydrofuran-3-yl)alnino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((tetrahydro-2H-pyran-4-yl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    3-((7-(N-(3-chloro-4-fluorophenyl)-N'-hydroxycarbamimidoyl)-4,5-difluoro-1H-benzo[d]imidazol-2-yl)amino)propanamide),
    N-(3-chloro-4-fluorophenyl)-2-((2-((2,2-difluoroethyl)amino)ethyl)amino)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-2-((2-(cyclopropyl(methyl)amino)ethyl)amino)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidarnide,
    N-(3-chloro-4-fluorophenyl)-2-((2-(cyclopropyl(2-methoxyethyl)amino)ethyl)amino)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    2-((2-(azetidin-1-yl)ethyl)amino)-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((3-methoxypropyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((2-(2-oxopyrrolidin-1-yl)ethyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((2-(morpholinosulfonyl)ethyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-2-((2-(3-fluoropiperidin-1-yl)ethyl)amino)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-bromo-4-fluorophenyl)-N'-hydroxy-2-((2-morpholinoethyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((2-(methyl(tetrahydro-2H-pyran-4-yl)amino)ethyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((2-(isopropyl(methyl)amino)ethyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    2-(((1-aminocyclopropyl)methyl)amino)-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    2-((2-(1-aminocyclopropyl)ethyl)amino)-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    2-((2-(2-oxa-5-azabicyclo[4.1.0]heptan-5-yl)ethyl)amino)-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    2-((2-(7-oxa-4-azaspiro[2.5]octan-4-yl)ethyl)amino)-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    (R)-(3-chloro-4-fluorophenyl)-2-((2-(3-fluoropyrrolidin-1-yl)ethyl)amino)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    (S)-(3-chloro-4-fluorophenyl)-2-((2-(3-fluoropyrrolidin-1-yl)ethyl)amino)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    2-((2-(2-azabicyclo[4.1.0]heptan-2-yl)ethyl)amino)-Ar-(3-chloro-4-fluorophenyl)-N-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    2-((2-(4-azaspiro[2.5]octan-4-yl)ethyl)amino)-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-2-((2-(3-fluoroazetidin-1-yl)ethyl)amino)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-2-((2-(3,3-difluoroazetidin-1-yl)ethyl)amino)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    2-((2-(4-azaspiro[2.4]heptan-4-yl)ethyl)amino)-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-2-((3-(3-fluoropiperidin-1-yl)propyl)amino)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((2-(phenylamino)ethyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((2-(methyl(phenyl)amino)ethyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-2-(((1,1-dioxidotetrahydro-2H-thiopyran-3-yl)methyl)amino)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-2-((2-ethoxycyclopropyl)amino)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-bromo-4-fluorophenyl)-N'-hydroxy-2-(methylamino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    2-(2-(azepan-1-yl)ethyl)-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    2-(2-(azetidin-1-yl)ethyl)-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    (R)-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(2-(3-hydroxypyrrolidin-1-yl)ethyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    (S)-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(2-(3-hydroxypyrrolidin-1-yl)ethyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(2-(4-hydroxypiperidin-1-yl)ethyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-bromo-4-fluorophenyl)-2-(2-(dimethylamino)ethyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-chlorophenyl)-2-(2-(dimethylamino)ethyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-bromophenyl)-2-(2-(dimethylamino)ethyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(2-(methylsulfonamido)ethyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(2-(sulfamoylamino)ethyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-chlorophenyl)-N'-hydroxy-2-(2-(pyrrolidin-1-yl)ethyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-bromophenyl)-N'-hydroxy-2-(2-(pyrrolidin-1-yl)ethyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(2-(7-(N-(3-chloro-4-fluorophenyl)-N'-hydroxycarbamimidoyl)-1H-imidazo[4,5-b]pyridin-2-yl)ethyl)acetamide,
    N-(3-chlorophenyl)-N'-hydroxy-2-(2-(piperidin-1-yl)ethyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-bromophenyl)-N'-hydroxy-2-(2-(piperidin-1-yl)ethyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    Methyl (2-(7-(N-(3-chloro-4-fluorophenyl)-N'-hydroxycarbamimidoyl)-1H-imidazo[4,5-b]pyridin-2-yl)ethyl)carbamate,
    N-(3-chloro-4-fluorophenyl)-2-(2-((2,4-dimethoxybenzyl)amino)ethyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    2-(2-(4-benzylpiperidin-1-yl)ethyl)-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    2-(2-(3-azabicyclo[3.3.1]nonan-3-yl)ethyl)-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    2-(2-(3-azabicyclo[3.2.1]octan-3-yl)ethyl)-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((1-methylpiperidin-3-yl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    (S)-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((2-(3-hydroxypyrrolidin-1-yl)ethyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    (S)-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(3-hydroxypyrrolidin-1-yl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((1-(2-methoxyethyl)pyrrolidin-3-yl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(((4-methylmorpholin-3-yl)methyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((2-(pyrrolidin-1-yl)ethyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(((4-((methylsulfonyl)methyl)tetrahydro-2H-pyran-4-yl)methyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((2-(methylsulfonyl)benzyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    2-((1-acetylpiperidin-3-yl)amino)-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-2-((ethylamino)methyl)-4-fluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-2-((dimethylamino)methyl)-4-fluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-4-fluoro-N'-hydroxy-2-((isopropylamino)methyl)-1H-benzo[d]imidazole-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-4-fluoro-N'-hydroxy-2-((methylamino)methyl)-1H-benzo[d]imidazole-7-carboximidamide,
    2-(aminomethyl)-N-(3-chloro-4-fluorophenyl)-4-fluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((2-hydroxy-2-methylpropylamino)-1H-benzo[d]imidazole-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((2-hydroxypropyl)amino)-1H-benzo[d]imidazole-7-carboximidamide,
    2-((7-(N-(3-chloro-4-fluorophenyl)-N'-hydroxycarbamimidoyl)-4,5-difluoro-1H-benzo[d]imidazol-2-yl)amino)acetamide,
    N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((2-hydroxyethyl)amino)-1H-benzo[d]imidazole-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((3-hydroxycyclobutyl)amino)-1H-benzo[d]imidazole-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((3-(pyridin-2-ylamino)propyl)amino)-1H-benzo[d]imidazole-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((2-sulfamoylethyl)amino)-1H-benzo[d]imidazole-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-(((1-methyl-1H-pyrazol-5-yl)methyl)amino)-1H-benzo[d]imidazole-7-carboximidamide,
    2-((2-(1H-pyrazol-1-yl)ethyl)amino)-N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide,
    2-((7-(N-(3-chloro-4-fluorophenyl)-N'-hydroxycarbamimidoyl)-4,5-difluoro-1H-benzo[d]imidazol-2-yl)amino)-N,N-dimethylacetamide,
    N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-(2-hydroxy-2-methylpropyl)-1H-benzo[d]imidazole-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-2-((4-(dimethylamino)butyl)amino)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((piperidin-3-ylmethyl)amino)-1H-benzo[d]imidazole-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((1-methylpiperidin-2-yl)methyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-bromophenyl)-N'-hydroxy-2-((2-morpholinoethyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-5-fluoro-N'-hydroxy-4-methoxy-1H-benzo[d]imidazole-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((pyridin-2-ylmethyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    2-((2-(1H-pyrazol-1-yl)ethyl)amino)-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(((1-methyl-1H-pyrazol-3-yl)methyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((4,4,4-trifluorobutyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((3,3,3-trifluoropropyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((2-(2-methoxyethoxy)ethyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-2-((3-(cyclopropyl(methyl)amino)propyl)amino)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-2-((3-(cyclopropylamino)propyl)amino)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-2-((3-(cyclopropyl(ethyl)amino)propyl)amino)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-2-((2-(4-fluoropiperidin-1-yl)ethyl)amino)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((2-(2,2,2-trifluoroethoxy)ethyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((3-(2,2,2-trifluoroethoxy)propyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((2-(3-methoxypiperidin-1-yl)ethyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-2-((3-(difluoromethoxy)propyl)amino)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    (R)-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(((tetrahydrofuran-2-yl)methyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    (S)-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(((tetrahydrofuran-2-yl)methyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((2-(tetrahydrofuran-2-yl)ethyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(piperidin-2-ylmethyl)-1H-imidazo[4,5-b]pyridine-7 -carboximidamide,
    N-(3-chloro-4-fluorophenyl)-2-(1-(dimethylamino)propan-2-yl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(2-(methylamino)propyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-2-(2-(dimethylamino)propyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(pyrrolidin-2-ylmethyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-chlorophenyl)-4,5-difluoro-N'-hydroxy-2-((2-(pyrrolidin-1-yl)ethyl)amino)-1H-benzo[d]imidazole-7-carboximidamide,
    N-(3-bromophenyl)-4,5-difluoro-N'-hydroxy-2-((2-(pyrrolidin-1-yl)ethyl)amino)-1H-benzo[d]imidazole-7-carboximidamide,
    N-(3-bromo-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((2-(pyrrolidin-1-yl)ethyl)amino)-1H-benzo[d]imidazole-7-carboximidamide,
    2-((2-aminoethyl)amino)-N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide,
    N-(2-((7-(N-(3-chloro-4-fluorophenyl)-N'-hydroxycarbamimidoyl)-4,5-difluoro-1H-benzo[d]imidazol-2-yl)amino)ethyl)acetamide,
    N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((2-(methylsulfonamido)ethyl)amino)-1H-benzo[d]imidazole-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-2-((2-(cyclopropanesulfonamido)ethyl)amino)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide,
    Methyl(2-((7-(N-(3-chloro-4-fluorophenyl)-N'-hydroxycarbamimidoyl)-4,5-difluoro-1H-benzo[d]imidazol-2-yl)amino)ethyl)carbamate,
    N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((2-(sulfamoylamino)ethyl)amino)-1H-benzo[d]imidazole-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((2-(phenylsulfonamido)ethyl)amino)-1H-benzo[d]imidazole-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-2-((2-cyanoethyl)amino)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-2-((2-(3-ethylureido)ethyl)amino)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((pyridin-2-ylmethyl)amino)-1H-benzo[d]imidazole-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((pyridin-3-ylmethyl)amino)-1H-benzo[d]imidazole-7-carboximidamide,
    2-(((1H-imidazol-2-yl)methyl)amino)-N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide,
    2-chloro-N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide,
    2-((2-aminobenzyl)amino)-N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-2-((2-(dimethylamino)benzyl)amino)-4,5-difluoro-N-hydroxy-1H-benzo[d]imidazole-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-(((1-methyl-1H-imidazol-2-yl)methyl)amino)-1H-benzo[d]imidazole-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((pyrimidin-2-ylmethyl)amino)-1H-benzo[d]imidazole-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-2-((3-(dimethylamino)-2,2-dimethylpropyl)amino)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-2-((3-(dimethylamino)-2-methylpropyl)amino)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-2-((3-(dimethylamino)butyl)amino)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((2-(1-methylpyrrolidin-2-yl)ethyl)amino)-1H-benzo[d]imidazole-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((2-(1-methylpiperidin-2-yl)ethyl)amino)-1H-benzo[d]imidazole-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-(((4-methylmorpholin-2-yl)methyl)amino)-1H-benzo[d]imidazole-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(((4-methylmorpholin-2-yl)methyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(((1-methyl-1H-pyrazol-5-yl)methyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    2-((7-(N-(3-chloro-4-Fluorophenyl)-N'-hydroxycarbamimidoyl)-1H-imidazo[4,5-b]pyridin-2-yl)amino)-N,N-dimethylacetamide,
    N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(3-(hydroxymethyl)azetidin-1-yl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((oxetan-3-ylmethyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((2-(1-methyl-1H-imidazol-2-yl)ethyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((3-(pyridin-2-ylamino)propyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidainide,
    N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(neopentylamino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(isobutylamino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(((tetrahydro-2H-pyran-2-yl)methyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(((tetrahydrofuran-3-yl)methyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-N'-hydroxy-N-methyl-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    2-amino-N-(3-chloro-4-fluorophenyl)-5-fluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide,
    2-amino-N-(3-chlorophenyl)-5-fluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide,
    2-amino-N-(3-bromophenyl)-5-fluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide,
    2-amino-N-(3-bromo-4-fluorophenyl)-5-fluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-2-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-2-((2-(diethylamino)ethyl)amino)-4-fluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-4-fluoro-N'-hydroxy-2-((2-(pyrrolidin-1-yl)ethyl)amino)-1H-benzo[d]imidazole-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((2-morpholinopropyl)amino)-1H-benzo[d]imidazole-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-2-((1-(dimethylamino)propan-2-yl)amino)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-2-((2-(dimethylamino)ethyl)amino)-5-fluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-5-fluoro-N'-hydroxy-2-((2-(pyrrolidin-1-yl)ethyl)amino)-1H-benzo[d]imidazole-7-carboximidamide,
    N-(3-chloro-4-fluoropbenyl)-2-((3-(dimethylamino)-2,2-dimethylpropyl)amino)-4-fluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide,
    N-(3-bromo-4-fluorophenyl)-2-((2-(dimethylamino)ethyl)amino)-4-fluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide,
    N-(3-bromophenyl)-2-((2-(dimethylamino)ethyl)amino)-4-fluoro-N-hydroxy-1H-benzo[d]imidazole-7-carboximidamide,
    N-(3-chlorophenyl)-2-((2-(dimethylamino)ethyl)amino)-4-fluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide,
    N-(3-chlorophenyl)-2-((3-(dimethylamino)propyl)amino)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide,
    N-(3-bromophenyl)-2-((3-(dimethylamino)propyl)amino)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide,
    N-(3-bromo-4-fluorophenyl)-2-((3-(dimethylamino)propyl)amino)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-2-((3-(dimethylamino)propyl)amino)-4-fluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-2-((3-(dimethylamino)propyl)amino)-5-fluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide,
    2-((2-(benzyl(methyl)amino)ethyl)amino)-N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-2-(2-((cyclohexylmethyl)(methyl)amino)ethyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(2-(methyl(neopentyl)amino)ethyl)-N'-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-2-(2-(cyclohexyl(methyl)amino)ethyl)N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((2-(methyl((tetrahydro-2H-pyran-4-yl)methyl)amino)ethyl)amino)-1H-benzo[d]imidazole-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((2-(methylamino)ethyl)amino)-1H-benzo[d]imidazole-7-carboximidamide,
    2-(2-(benzyl(methyl)amino)ethyl)-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-2-((2-((2-ethylbutyl)(methyl)amino)ethyl)amino)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-2-((2-((cyclopropylmethyl)(methyl)amino)ethyl)amino)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(2-(methyl((tetrahydro-2H-pyran-4-yl)methyl)amino)ethyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    2-(2-(((1,4-dioxan-2-yl)methyl)(methyl)amino)ethyl)-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(2-(methyl(2-(tetrahydro-2H-pyran-4-yl)ethyl)amino)ethyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-2-((2-(cyclopropylamino)ethyl)amino)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-2-((2-(cyclopropyl(ethyl)amino)ethyl)amino)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(2-((7-(N-(3-chloro-4-fluorophenyl)-N'-hydroxycarbamimidoyl)-1H-imidazo[4,5-b]pyridin-2-yl)amino)ethyl)acetamide,
    N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((2-(methylsulfonamido)ethyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-2-((2-(cyclopropyl(isopropyl)amino)ethyl)amino)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-2-((2-(cyclopropyl(2-hydroxyethyl)amino)ethyl)amino)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    2-((2-aminoethyl)amino)-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(((5-oxopyrrolidin-3-yl)methyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    2-(((1H-pyrazol-5-yl)methyl)amino)-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-((7-(N-(3-chloro-4-fluorophenyl)-N'-hydroxycarbamimidoyl)-1H-imidazo[4,5-b]pyridin-2-yl)amino)propyl)acetamide,
    2-((3-aminopropyl)amino)-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-chloro-4-Fluorophenyl)-N'-hydroxy-2-((2-(sulfamoylamino)ethyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((2-(phenylsulfonamido)ethyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    Methyl (2-((7-(N-(3-chloro-4-fluorophenyl)-N'-hydroxycarbamimidoyl)-1H-imidazo[4,5-b]pyridin-2-yl)amino)ethyl)carbamate,
    N-(3-chloro-4-fluorophenyl)-2-((2-(cyclopropanesulfonamido)ethyl)amino)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((2-((trifluoromethyl)sulfonamido)ethyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    2-(((1H-imidazol-2-yl)methyl)amino)-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    2-(((1H-imidazol-5-yl)methyl)amino)-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(((3-methyl-1,2,4-oxadiazol-5-yl)methyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-bromophenyl)-N'-hydroxy-2-(methylamino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    Methyl (3-((7-(N-(3-chloro-4-fluorophenyl)-N'-hydroxycarbamimidoyl)-1H-imidazo[4,5-b]pyridin-2-yl)amino)propyl)carbamate,
    N-(3-bromophenyl)-N'-hydroxy-2-methoxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-bromophenyl)-N'-hydroxy-2-((2-(methylsulfonyl)ethyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-bromophenyl)-N'-hydroxy-2-((2-(methylsulfonamido)ethyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-bromophenyl)-N'-hydroxy-2-((2-sulfamoylethyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(((5-methyl-1,3,4-oxadiazol-2-yl)methyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-(((1-methylpiperidin-2-yl)methyl)amino)-1H-benzo[d]imidazole-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-(((4-methylmorpholin-3-yl)methyl)amino)-1H-benzo[d]imidazole-7-carboximidamide,
    N-(3-bromophenyl)-2-((2-(dimethylamino)ethyl)amino)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide,
    N-(3-chlorophenyl)-2-((2-(dimethylamino)ethyl)amino)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide,
    N-(3-bromo-4-fluorophenyl)-2-((2-(dimethylamino)ethyl)amino)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-4,5-difluoro-2-((3-morpholinopropyl)amino)-1H-benzo[d]imidazole-7-carboxamide,
    N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((3-(pyrrolidin-1-yl)propyl)amino)-1H-benzo[d]imidazole-7-carboximidamide,
    2-(((3R)-4-amino-1-methylpyrrolidin-3-yl)amino)-N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-2-((2-(dimethylamino)-2-phenylethyl)amino)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-2-(((1R,2R)-2-(dimethylamino)cyclohexyl)amino)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-2-(((1-(dimethylamino)cyclopentyl)methyl)amino)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-2-(((1S,3S)-3-(dimethylamino)cyclohexyl)amino)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-2-(((1S,3R)-3-(dimethylamino)cyclohexyl)amino)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-2-(((1-(dimethylamino)cyclobutyl)methyl)amino)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((1-methylpiperidin-4-yl)amino)-1H-benzo[d]imidazole-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((1-methylpiperidin-3-yl)amino)-1H-benzo[d]imidazole-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-2-(((1S,2S)-2-(dimethylamino)cyclohexylamino)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide,
    (S)-N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-(piperidin-3-ylamino)-1H-benzo[d]imidazole-7-carboximidamide,
    (R)-N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-(piperidin-3-ylamino)-1H-benzo[d]imidazole-7-carboximidamide,
    (S)-N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((1-methylpyrrolidin-3-yl)amino)-1H-benzo[d]imidazole-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-2-((3-(dimethylamino)-2-hydroxypropyl)amino)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((2-(4-methyl-3-oxopiperazin-1-yl)ethyl)amino)-1H-benzo[d]imidazole-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-2-(((1-(dimethylamino)cyclohexyl)methyl)amino)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((1-methylazepan-3-yl)amino)-1H-benzo[d]imidazole-7-carboximidamide,
    (S)-N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((2-(3-hydroxypyrrolidin-1-yl)ethyl)amino)-1H-benzo[d]imidazole-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((1-(2-methoxyethyl)piperidin-3-yl)amino)-1H-benzo[d]imidazole-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((1-(2-methoxyethyl)pyrrolidin-3-yl)amino)-1H-benzo[d]imidazole-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((1-isopropylpiperidin-3-yl)amino)-1H-benzo[d]imidazole-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((2-(3-methoxyazetidin-1-yl)ethyl)amino)-1H-benzo[d]imidazole-7-carboximidamide,
    (R)-N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((1-methylpyrrolidin-3-yl)amino)-1H-benzo[d]imidazole-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-(((3R,4R)-4-methoxy-1-methylpyrrolidin-3-yl)amino)-1H-benzo[d]imidazole-7-carboximidamide,
    (S)-N-(3-chlorophenyl)-4,5-difluoro-N'-hydroxy-2-((1-methylpiperidin-3-yl)amino)-1H-benzo[d]imidazole-7-carboximidamide,
    (R)-N-(3-chlorophenyl)-4,5-difluoro-N'-hydroxy-2-((1-methylpiperidin-3-yl)amino)-1H-benzo[d]imidazole-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-2-((2-(dimethylamino)cyclopentyl)amino)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide,
    (S)-2-(azepan-3-ylamino)-N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide,
    (R)-2-(azepan-3-ylamino)-N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-(pyrrolidin-3-ylamino)-1H-benzo[d]imidazole-7-carboximidamide,
    (R)-N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((1-(oxetan-3-yl)piperidin-3-yl)amino)-1H-benzo[d]imidazole-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-2-(((1,4-dimethylpiperidin-2-yl)methyl)amino)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((morpholin-3-ylmethyl)amino)-1H-benzo[d]imidazole-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-(((3R,4S)-4-hydroxypyrrolidin-3-yl)amino)-1H-benzo[d]imidazole-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-(((1R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl)amino)-1H-benzo[d]imidazole-7-carboximidamide,
    (S)-N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((2-(2-(trifluoromethyl)pyrrolidin-1-yl)ethyl)amino)-1H-benzo[d]imidazole-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-4,5-difluoro-2-(((hexahydro-1H-pyrrolizin-7a-yl)methyl)amino)-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-2-(((3,3-dimethylazetidin-2-yl)methyl)amino)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((4-(pyrrolidin-1-yl)tetrahydro-2H-pyran-3-yl)amino)-1H-benzo[d]imidazole-7-carboximidamide,
    2-(((1S,2R)-2-aminocyclohexyl)amino)-N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)amino)-1H-benzo[d]imidazole-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-2-(((3S,4S)-4-(diethylamino)tetrahydrofuran-3-yl)amino)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide,
    2-((1,4-oxazepan-6-yl)amino)-N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide.
    N-(3-chloro-4-fluorophenyl)-2-((2-((2S,6R)-2,6-dimethylmorpholino)ethyl)amino)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(((3R,4R)-4-methoxy-1-methylpyrrolidin-3-yl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-2-(((3R,4R)-4-(diethylamino)tetrahydrofuran-3-yl)amino)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    (S)-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((2-(2-(trifluoromethyl)pyrrolidin-1-yl)ethyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    (R)-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(((4-methylmorpholin-3-yl)methyl)amino-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-2-((2-(2,6-dimethylmorpholino)propyl)amino)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-chloro-4-Fluorophenyl)-2-((2-(2,6-dimethylmorpholino)-2-methylpropyl)amino)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-2-((2-(2,5-dimethylmorpholino)ethyl)amino)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-2-(((1R,2R)-2-(dimethylamino)cyclopentyl)amino)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-2-((2-(dimethylamino)ethyl)thio)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-2-((2-(dimethylamino)ethyl)thio)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((2-(2-(hydroxymethyl)piperidin-1-yl)ethyl)amino)-1H-benzo[d]imidazole-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((2-(2-(hydroxymethyl)pyrrolidin-1-yl)ethyl)amino)-1H-benzo[d]imidazole-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-2-((2-(3,3-difluoropyrrolidin-1-yl)ethyl)amino)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((2-sulfamoylethyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((2-(methylsulfonyl)ethyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((pyrimidin-2-ylmethyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    (R)-N-(3-chlorophenyl)-4,5-difluoro-N'-hydroxy-2-((1-(2-methoxyethyl)pyrrolidin-3-yl)amino)-1H-benzo[d]imidazole-7-carboximidamide,
    (R)-N-(3-bromophenyl)-4,5-difluoro-N'-hydroxy-2-((1-(2-methoxyethyl)pyrrolidin-3-yl)amino)-1H-benzo[d]imidazole-7-carboximidamide,
    (S)-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((1-(oxetan-3-yl)piperidin-3-yl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((1-(2-methoxyethyl)piperidin-3-yl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-2-((1-cyclopropylpyrrolidin-3-yl)amino)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    (R)-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((1-(oxetan-3-yl)piperidin-3-yl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((2-(4-methyl-3-oxopiperazin-1-yl)ethyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-2-((2-(3,3-difluoropiperidin-1-yl)ethyl)amino)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    2-((1-acetylpyrrolidin-3-yl)amino)-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((1-(methylsulfonyl)pyrrolidin-3-yl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((3-(methylsulfonyl)propyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-2-(((1,1-dioxidotetrahydrothiophen-3-yl)methyl)amino)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide,
    N-(3-chloro-4-fluorophenyl)-2-((3-((4-fluorophenyl)sulfonyl)propyl)amino)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide, and
    (R)-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((1-(oxetan-3-yl)pyrrolidin-3-yl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide;
    or a pharmaceutically acceptable salt or mixture thereof.
  13. A pharmaceutical composition comprising a compound of any one of claims 1 to 12 or a pharmaceutically acceptable salt or mixture thereof, and at least one pharmaceutically acceptable vehicle.
  14. A compound of any one of claims 1 to 12 or a pharmaceutically acceptable salt or mixture thereof for use in
    (I) a method of treating a human, who has or is suspected of having a disease or condition responsive or believed to be responsive to the inhibition of IDO1 activity;
    (II) a method of inhibiting the activity of an IDO1 protein;
    (III) a method of inhibiting growth or a proliferation of cancer cells;
    (IV) a method of inhibiting immunosuppression in a patient; or
    (V) a method of treating cancer, viral infection, depression, a neurodegenerative disorder, trauma, age-related cataracts, organ transplant rejection, or an autoimmune disease in a patient.
  15. The compound for use of claim 14(V) wherein the method further comprises administering to said patient an anti-viral agent, a chemotherapeutic, an immunosuppressant, radiation, an anti-tumor vaccine, an antiviral vaccine, cytokine therapy, or a tyrosine kinase inhibitor, such as an HBV inhibitor or an HIV inhibitor.
  16. The compound, a pharmaceutically acceptable salt or a mixture thereof of any of claims 1-12 for use in therapy.
EP16730065.6A 2015-05-15 2016-05-12 Benzimidazole and imadazopyridine carboximidamide compounds having activity as inhibitors of indoleamine 2,3-dioxygenase Active EP3294732B1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201562162531P 2015-05-15 2015-05-15
PCT/US2016/032152 WO2016186967A1 (en) 2015-05-15 2016-05-12 Benzimidazole and imadazopyridine carboximidamide compounds having activity as inhibitors of indoleamine 2,3-dioxygenase

Publications (2)

Publication Number Publication Date
EP3294732A1 EP3294732A1 (en) 2018-03-21
EP3294732B1 true EP3294732B1 (en) 2019-09-25

Family

ID=56134561

Family Applications (1)

Application Number Title Priority Date Filing Date
EP16730065.6A Active EP3294732B1 (en) 2015-05-15 2016-05-12 Benzimidazole and imadazopyridine carboximidamide compounds having activity as inhibitors of indoleamine 2,3-dioxygenase

Country Status (17)

Country Link
US (1) US9951065B2 (en)
EP (1) EP3294732B1 (en)
JP (2) JP2018515541A (en)
KR (1) KR20180004811A (en)
CN (1) CN107849024A (en)
AR (1) AR104642A1 (en)
AU (1) AU2016263083B2 (en)
BR (1) BR112017024331A2 (en)
CA (1) CA2985642A1 (en)
EA (1) EA201792259A1 (en)
ES (1) ES2761824T3 (en)
HK (2) HK1244796A1 (en)
IL (1) IL255294A0 (en)
MX (1) MX2017014613A (en)
NZ (1) NZ736709A (en)
TW (1) TWI657079B (en)
WO (1) WO2016186967A1 (en)

Families Citing this family (24)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB201311888D0 (en) 2013-07-03 2013-08-14 Glaxosmithkline Ip Dev Ltd Novel compounds
GB201311891D0 (en) 2013-07-03 2013-08-14 Glaxosmithkline Ip Dev Ltd Novel compound
BR112017013858A2 (en) 2014-12-26 2018-02-27 Univ Emory n4-hydroxycytidine and related antiviral derivatives and uses
CN106905256A (en) * 2017-03-06 2017-06-30 中国药科大学 Benzo five-membered heterocyclic IDO1 inhibitor, its preparation method and application
JOP20180040A1 (en) 2017-04-20 2019-01-30 Gilead Sciences Inc Pd-1/pd-l1 inhibitors
EP3661909B1 (en) * 2017-08-02 2023-08-16 Merck Sharp & Dohme LLC Novel substituted phenyl compounds as indoleamine 2,3-dioxygenase (ido) inhibitors
WO2019027856A1 (en) 2017-08-02 2019-02-07 Merck Sharp & Dohme Corp. Novel substituted pyridine compounds as indoleamine 2,3-dioxygenase (ido) inhibitors
KR102626210B1 (en) 2017-12-07 2024-01-18 에모리 유니버시티 N4-hydroxycytidine and derivatives and anti-viral uses related thereto
EP3747875B1 (en) * 2018-02-02 2022-12-07 Hinova Pharmaceuticals Inc. Indoleamine-2,3-dioxygenase inhibitor, preparation method therefor and use thereof
PL3752501T3 (en) 2018-02-13 2023-08-21 Gilead Sciences, Inc. Pd-1/pd-l1 inhibitors
EP3781556A1 (en) 2018-04-19 2021-02-24 Gilead Sciences, Inc. Pd-1/pd-l1 inhibitors
UA125163C2 (en) 2018-05-14 2022-01-19 Гіліад Сайєнсіз, Інк. Mcl-1 inhibitors
JP7199502B2 (en) * 2018-07-06 2023-01-05 ギリアード サイエンシーズ， インコーポレイテッド Therapeutic heterocyclic compounds
PT3820572T (en) 2018-07-13 2023-11-10 Gilead Sciences Inc Pd-1/pd-l1 inhibitors
US11987579B2 (en) * 2018-07-30 2024-05-21 Duke University Niclosamide analogues and therapeutic use thereof
US11236085B2 (en) 2018-10-24 2022-02-01 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
CN110054627B (en) * 2019-01-10 2020-06-30 北京华氏开元医药科技有限公司 Novel IDO inhibitor, preparation method, pharmaceutical composition and application thereof
CR20220316A (en) 2019-12-06 2022-10-07 Vertex Pharma Substituted tetrahydrofurans as modulators of sodium channels
CN111153850B (en) * 2020-01-17 2021-08-13 中国药科大学 Indole compound, preparation method thereof, pharmaceutical composition and application
PE20231744A1 (en) * 2020-08-07 2023-10-31 Italfarmaco Spa NEW OXADIAZOLE-BASED SELECTIVE HDAC6 INHIBITORS
CN112898206A (en) * 2021-02-05 2021-06-04 河北凡博医药科技有限公司 Preparation method of 5, 6-dimethylbenzimidazole
BR112023017582A2 (en) 2021-03-05 2023-12-05 Univ Basel COMPOSITIONS FOR THE TREATMENT OF DISEASES OR CONDITIONS ASSOCIATED WITH EBV
EP4052705A1 (en) 2021-03-05 2022-09-07 Universität Basel Vizerektorat Forschung Compositions for the treatment of ebv associated diseases or conditions
CN117794920A (en) 2021-06-04 2024-03-29 沃泰克斯药物股份有限公司 N- (hydroxyalkyl (hetero) aryl) tetrahydrofurancarboxamides as sodium channel modulators

Family Cites Families (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5643935A (en) * 1995-06-07 1997-07-01 The University Of North Carolina At Chapel Hill Method of combatting infectious diseases using dicationic bis-benzimidazoles
CA2634198C (en) * 2005-12-20 2014-06-03 Incyte Corporation N-hydroxyamidinoheterocycles as modulators of indoleamine 2,3-dioxygenase
CN101415702B (en) * 2006-04-03 2011-08-10 安斯泰来制药有限公司 Hetero compound
US20080119491A1 (en) * 2006-09-19 2008-05-22 Incyte Corporation Amidinoheterocycles as modulators of indoleamine 2,3-dioxygenase
EP2139478A4 (en) * 2007-03-30 2010-05-05 Cytokinetics Inc Certain chemical entities, compositions and methods
JP2016028016A (en) * 2012-12-12 2016-02-25 大日本住友製薬株式会社 Oxadiazole derivatives and pharmaceutical uses thereof
US9617272B2 (en) * 2013-03-14 2017-04-11 Newlink Genetics Corporation Tricyclic compounds as inhibitors of immunosuppression mediated by tryptophan metabolization
TWI527811B (en) * 2013-05-09 2016-04-01 吉李德科學股份有限公司 Benzimidazole derivatives as bromodomain inhibitors
ES2719327T3 (en) * 2013-07-01 2019-07-09 Bristol Myers Squibb Co IDO inhibitors

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
None *

Also Published As

Publication number Publication date
TW201706251A (en) 2017-02-16
US9951065B2 (en) 2018-04-24
MX2017014613A (en) 2018-03-01
EP3294732A1 (en) 2018-03-21
EA201792259A1 (en) 2018-06-29
TWI657079B (en) 2019-04-21
JP2019070042A (en) 2019-05-09
IL255294A0 (en) 2017-12-31
CA2985642A1 (en) 2016-11-24
WO2016186967A1 (en) 2016-11-24
KR20180004811A (en) 2018-01-12
NZ736709A (en) 2019-05-31
HK1248235A1 (en) 2018-10-12
AU2016263083A1 (en) 2017-11-16
US20160333009A1 (en) 2016-11-17
JP2018515541A (en) 2018-06-14
BR112017024331A2 (en) 2018-07-24
AU2016263083B2 (en) 2019-04-04
ES2761824T3 (en) 2020-05-21
AR104642A1 (en) 2017-08-02
HK1244796A1 (en) 2018-08-17
CN107849024A (en) 2018-03-27

Similar Documents

Publication Publication Date Title
EP3294732B1 (en) Benzimidazole and imadazopyridine carboximidamide compounds having activity as inhibitors of indoleamine 2,3-dioxygenase
AU2018319538B9 (en) Therapeutic heterocyclic compounds
AU2019297428B2 (en) Therapeutic heterocyclic compounds
AU2019297362B2 (en) Therapeutic heterocyclic compounds

Legal Events

Date Code Title Description
STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE INTERNATIONAL PUBLICATION HAS BEEN MADE

PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: REQUEST FOR EXAMINATION WAS MADE

17P Request for examination filed

Effective date: 20171208

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

AX Request for extension of the european patent

Extension state: BA ME

REG Reference to a national code

Ref country code: HK

Ref legal event code: DE

Ref document number: 1244796

Country of ref document: HK

DAV Request for validation of the european patent (deleted)
DAX Request for extension of the european patent (deleted)
GRAP Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOSNIGR1

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: GRANT OF PATENT IS INTENDED

INTG Intention to grant announced

Effective date: 20181025

GRAJ Information related to disapproval of communication of intention to grant by the applicant or resumption of examination proceedings by the epo deleted

Free format text: ORIGINAL CODE: EPIDOSDIGR1

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: REQUEST FOR EXAMINATION WAS MADE

INTC Intention to grant announced (deleted)
GRAP Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOSNIGR1

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: GRANT OF PATENT IS INTENDED

INTG Intention to grant announced

Effective date: 20190411

GRAS Grant fee paid

Free format text: ORIGINAL CODE: EPIDOSNIGR3

GRAA (expected) grant

Free format text: ORIGINAL CODE: 0009210

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE PATENT HAS BEEN GRANTED

AK Designated contracting states

Kind code of ref document: B1

Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

REG Reference to a national code

Ref country code: GB

Ref legal event code: FG4D

REG Reference to a national code

Ref country code: CH

Ref legal event code: EP

REG Reference to a national code

Ref country code: AT

Ref legal event code: REF

Ref document number: 1183710

Country of ref document: AT

Kind code of ref document: T

Effective date: 20191015

REG Reference to a national code

Ref country code: IE

Ref legal event code: FG4D

REG Reference to a national code

Ref country code: DE

Ref legal event code: R096

Ref document number: 602016021243

Country of ref document: DE

REG Reference to a national code

Ref country code: NL

Ref legal event code: MP

Effective date: 20190925

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SE

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20190925

Ref country code: BG

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20191225

Ref country code: HR

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20190925

Ref country code: LT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20190925

Ref country code: FI

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20190925

Ref country code: NO

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20191225

REG Reference to a national code

Ref country code: LT

Ref legal event code: MG4D

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: GR

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20191226

Ref country code: RS

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20190925

Ref country code: LV

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20190925

REG Reference to a national code

Ref country code: DE

Ref legal event code: R082

Ref document number: 602016021243

Country of ref document: DE

Representative=s name: ZWICKER SCHNAPPAUF & PARTNER PATENTANWAELTE PA, DE

REG Reference to a national code

Ref country code: AT

Ref legal event code: MK05

Ref document number: 1183710

Country of ref document: AT

Kind code of ref document: T

Effective date: 20190925

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: AL

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20190925

Ref country code: PT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20200127

Ref country code: RO

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20190925

Ref country code: NL

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20190925

Ref country code: AT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20190925

Ref country code: PL

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20190925

Ref country code: EE

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20190925

REG Reference to a national code

Ref country code: ES

Ref legal event code: FG2A

Ref document number: 2761824

Country of ref document: ES

Kind code of ref document: T3

Effective date: 20200521

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: IS

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20200224

Ref country code: SK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20190925

Ref country code: SM

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20190925

Ref country code: CZ

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20190925

REG Reference to a national code

Ref country code: DE

Ref legal event code: R097

Ref document number: 602016021243

Country of ref document: DE

PG2D Information on lapse in contracting state deleted

Ref country code: IS

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: DK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20190925

Ref country code: IS

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20200126

PLBE No opposition filed within time limit

Free format text: ORIGINAL CODE: 0009261

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT

26N No opposition filed

Effective date: 20200626

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SI

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20190925

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: LI

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20200531

Ref country code: CH

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20200531

Ref country code: MC

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20190925

REG Reference to a national code

Ref country code: BE

Ref legal event code: MM

Effective date: 20200531

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: LU

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20200512

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: BE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20200531

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: TR

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20190925

Ref country code: MT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20190925

Ref country code: CY

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20190925

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: MK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20190925

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: IT

Payment date: 20230412

Year of fee payment: 8

Ref country code: ES

Payment date: 20230605

Year of fee payment: 8

Ref country code: DE

Payment date: 20230314

Year of fee payment: 8

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: IE

Payment date: 20240312

Year of fee payment: 9

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: GB

Payment date: 20240321

Year of fee payment: 9

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: FR

Payment date: 20240308

Year of fee payment: 9